Systematic review: how effective are the usual treatments for
ulcerative colitis?
J . R. BEBB & B. B. SCOTT
Department of Gastroenterology, Lincoln County Hospital, Lincoln, UK
Accepted for publication 3 May 2004
SUMMARY
Background: Details of the efficacy of the drugs used in
ulcerative colitis are not readily available.
Methods: We have reviewed all placebo-controlled trials
of the commonly used drugs for both induction and
maintenance of remission to determine the efficacy and
to calculate the numbers needed to treat (NNTs) to
achieve a specified benefit for each drug.
Results: The drug response rates and the NNTs (with
95% CI) are tabulated for each drug.
Conclusion: Corticosteroids give a remission rate of 68%
in mild or moderate disease and an NNT for remission of
2 (95% CI 1.4–5) in mild disease. Intravenous hydro-
cortisone gives a remission rate of 60–73%. Aminosal-
icylates are relatively ineffective in inducing remission
with an NNT of 10 (95% CI 7–21) improving to 8 (95%
CI 5–20) if the dose ‡3 g daily. They are better at
maintenance (NNT ¼ 6; 95% CI 4–8). Intravenous
ciclosporin is very effective in achieving remission in
severe colitis with an NNT of 1.2 (95% CI 1–2.5).
Although there is fairly good evidence that azathioprine
is effective in maintaining remission and is used widely,
there are no suitable placebo-controlled trials to calcu-
late the NNT.
INTRODUCTION
In December 2003 a vice president of GlaxoSmithKline
caused a furore in the media when he told a scientific
meeting in London that the vast majority of drugs only
work in 30–50% of people.1 That such a statement can
cause a furore suggests that most people have the belief
that most drugs work in most people. Indeed most
clinicians hold the naı¨ve belief that the drug they are
prescribing will work and they usually do not prepare
themselves or their patient for the possibility of failure.
Of course, this has the advantage of improving
response; we all tend to respond better to a treatment
if we have faith in it. However, we also need to be
honest with our patients especially when they ask about
the benefits of a proposed treatment. Doctors also need
to be aware of likely efficacy of treatments when
balancing risks and benefits. The purpose of this paper
is to reveal the efficacy of drugs used in colitis.
There are relatively few drug treatments that gastro-
enterologists in a nonresearch environment use to
induce and maintain remission of ulcerative colitis.
These can be split into the following: corticosteroids
(hydrocortisone and prednisolone); aminosalicylates or
5-ASA-based drugs (including sulfasalazine, mesalazine,
olsalazine and balsalazide); azathioprine (AZA) and its
active constituent mercaptopurine (MP) and ciclosporin.
In our local practice, we routinely provide patients
with information sheets on the commonly prescribed
treatments, with data such as side-effects, important
interactions etc. We have not hitherto informed our
patients, or ourselves, of the likely benefits (over placebo
or no treatment) of taking the treatments we recom-
mend, either in achieving remission or maintaining it.
Correspondence to: Dr B. B. Scott, Department of Gastroenterology, Lincoln
County Hospital, Lincoln, LN2 5QY, UK.
E-mail: drbbscott@aol.com
Aliment Pharmacol Ther 2004; 20: 143–149. doi: 10.1111/j.1365-2036.2004.02018.x
� 2004 Blackwell Publishing Ltd 143
To correct this omission we have reviewed all placebo-
controlled trials of drugs commonly used in ulcerative
colitis and calculated an expected remission rate (or
maintenance of remission rate) for placebo and the
particular drug. Based on these data we have calculated
the number needed to treat (NNT) for each treatment to
induce or maintain remission. Where insufficient pla-
cebo-controlled data exist, we have given a ‘best guess’
as to the expected remission rate with the drug, based
on nonplacebo-controlled data.
METHODS
A computer-assisted search using the OVID interface to
MEDLINE was conducted to identify potentially relevant
published papers. A search of theMEDLINE database from
1966 to 2003 was performed using the terms ‘ulcerative
colitis’, ‘placebo’ and the names of the following drugs:
‘corticosteroids’, ‘hydrocortisone’, ‘prednisolone’, ‘sulfa-
salazine’, ‘mesalazine’, ‘olsalazine’, ‘balsalazide’, ‘az-
athioprine’, and ‘mercaptopurine’. We also identified
further trials from lists of references and expert reviews,
including the Cochrane Library. We obtained and
reviewed all references and deduced placebo and drug-
induced remission rateswhere possible.We only included
‘intention-to-treat’ data, and used symptomatic patient
based endpoints as a judge of induction of remission or
maintenance, rather than artificial scoring systems or
endoscopic gradings, as we felt this was the information
that patients would wish to know. In some situations it
was possible to include data on clinical improvement
(without necessarily induction of remission) and we
included this as we felt it would be useful. For each study
we calculated an expected NNT by subtracting the
placebo response rate from the drug response rate and
dividing 100 by the percentage difference (95% confid-
ence intervals were estimated using the Newcombe
method). We have separated results by drug, induction
or maintenance of remission and, in some cases, by
dosage (e.g. low vs. standard or high dose 5-ASA).
RESULTS
Corticosteroids
We could only identify two placebo-controlled trials of
corticosteroids in the treatment of ulcerative colitis
(Table 1).2, 3 Both studies were published over 40 years
ago and one2 uses a form of corticosteroid (cortisone)
not prescribed in current practice. To provide further
information on the efficacy of corticosteroids we have
examined data on the course or ‘natural history’ of
ulcerative colitis in the precorticosteroid era, and other
nonplacebo-controlled data.
Before the introduction of corticosteroids in the
treatment of ulcerative colitis in the early 1950s
patients received supportive medical treatment inclu-
ding high-calorie low-residue diet, vitamin supplements,
superficial psychotherapy and, on occasion, psychiatric
evaluation and treatment in the event of serious
emotional disturbance.4 Mortality rates were high in
the early 20th century ranging from 8 to 55%.5 In a
review of 129 patients treated at the Radcliffe Infirmary,
Oxford, between 1938 and 1948, 22% of patients with
their first attack died.6 Interestingly, 69% of newly
presented colitic patients in this study, who did not
receive the treatment of the day (penicillin and/or
sulphonamides), were symptom-free or had a ‘fair
response’ with supportive measures alone. This is
perhaps the best data we will ever have on the
untreated course of ulcerative colitis at initial presen-
tation. Further follow-up of patients treated in Oxford7
after 1953 (when corticosteroids were first being used)
showed that patients in their first attack were much less
likely to die (6.9% with treatment, 27.3% without) if
they had received a specific medical treatment (such as
adrenocorticotrophic hormone or corticosteroids).
Current management of severe attacks of ulcerative
colitis involves inpatient admission, i.v. hydrocortisone
and, often, prednisolone enemas. There are no placebo-
controlled trials of these treatments but nonplacebo-
controlled trials from the 1970s8, 9 show remission
Table 1. Studies of corticosteroids vs. placebo in the treatment of active ulcerative colitis
Study Drug Treatment
duration
Placebo remission
rate
Drug remission
rate
Number needed to
treat (95% CI)
Truelove 19542
moderate-severe colitis
Cortisone 100 mg
initial dose orally
6 weeks 16/101 (15.8%) 45/109 (41.3%) 4 (3–7)
Lennard-Jones 19603
mild colitis
Prednisone 40–60 mg 3–4 weeks 3/18 (17%) 13/19 (68%) 2 (1.4–5)
144 J. R. BEBB & B. B. SCOTT
� 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20, 143–149
rates of 60–73% with 75–81% either improved or in
remission. Similar results have been obtained in other
centres.10
Inpatient admission for i.v. hydrocortisone is not
commonly required for exacerbations of UC, and many
patients with mild to moderate exacerbations can be
managed as outpatients with oral prednisolone. There
are no placebo-controlled trials of oral prednisolone but,
from placebo-controlled trials using prednisone
(in equivalent dosages3) and noncontrolled studies,11
we can expect a remission rates of at least 65% with
doses of at least 40 mg.
Aminosalicylates (5-ASA preparations)
Induction of remission in active colitis. We identified nine
placebo-controlled trials of 5-ASA compounds in the
treatment of active ulcerative colitis,12–20 (Table 2)
helped by the Cochrane Library.21 None studied sulfa-
salazine. Over 1200 patients have been included in
these studies. A variety of preparations have been used
in differing doses, but all in patients with mild to
moderately active disease. For some of the studies data is
available on improvement or remission, as opposed to
induction of remission alone. For induction of remission
we calculated an expected placebo remission rate of
10%, with 5-ASA compounds inducing remission in
only 20%, giving an NNT of 10 (95% CI 7–21). When
data including clinical improvement was added these
rates improve to 34% for placebo and 58% for 5-ASA
giving an NNT of 4 (95% CI 3–6). When data was split
into what would now be considered low dose 13, 18, 19
and standard or high dose, little difference is made to
the NNT. These calculations confirm our experience
that 5-ASA alone is usually unsatisfactory in inducing
remission in active disease.
Maintenance of remission in ulcerative colitis. We identi-
fied eight placebo-controlled trials of 5-ASA in main-
tenance of remission in ulcerative colitis,22–29 including
three using sulfasalazine (Table 3). Follow-up was
between 6 months and 1 year. Thirty-eight per cent of
Table 2. Studies of 5-ASA vs. placebo in the treatment of active ulcerative colitis
Study Drug
Duration
(weeks)
Placebo Drug
Number needed to
treat (95% CI)
Remission
(%)
Remission or
improvement (%)
Remission
(%)
Remission or
improvement (%) Remission
Remission or
improvement
Hetzel 198612 Olsalazine 2 6 2/15 (13) 6/15 (40) 4
Schroeder 198713 Asacol 6 2/38 (5) 7/38 (18)
1.6 g 1/11 (9) 3/11 (27) 26 11
4.8 g 9/38 (24) 28/38 (74) 5 2
Robinson 198814 Olsalazine 3 g 4 14/48 (29) 21/50 (42) 8
Feurle 198915 Olsalazine 2 g 4 24/53 (45) 27/52 (52) 14
Zinberg 199016 Olsalazine 3 g 4 2/8 (25) 4/7 (57) 3
Sutherland 199017 Rowasa 6 8/44 (18)
2 g 8/45 (18) –
4 g 21/47 (45) 4
Sninsky 199118 Asacol 6 2/52 (4) 10/52 (19)
1.6 g 6/53 (11) 19/53 (36) 13 6
2.4 g 6/53 (11) 21/53 (40) 13 5
Hanauer 199319 Pentasa 8 11/90 (12) 49/90 (54)
1 g 19/92 (21) 65/92 (71) 12 6
2 g 28/97 (29) 77/97 (79) 6 4
4 g 28/95 (29) 80/95 (84) 6 3
Hanauer 199620 Olsalazine 12 12/90 (13)
2–2.9 g 11/92 (12) –
‡3 g 16/91 (18) 24
Overall All doses 27/270 (10) 116/348 (33) 124/622 (20) 380/655 (58) 10 (7–21) 4 (3–5)
<2 g 15/180 (8) 66/180 (37) 26/156 (17) 87/156 (56) 12 (6–79) 5 (3–12)
2–2.9 g 25/232 (11) 93/254 (37) 45/242 (19) 139/262 (53) 13 (7–70) 6 (4–13)
‡3 g 25/218 (11) 80/228 (35) 53/224 (24) 154/237 (65) 8 (5–20) 3 (3–5)
SYSTEMATIC REVIEW: DRUG EFFECTIVENESS IN ULCERATIVE COLITIS 145
� 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20, 143–149
patients on placebo can be expected to be in remission
after this time period as opposed to 56% on 5-ASA,
giving an NNT of 5 (95% CI 4–8). Higher remission
rates were achieved in the original trials using sulfasal-
azine, but this benefit (compared with more modern
preparations) did not reach statistical significance.
Azathioprine/6MP
Azathioprine is increasingly used by gastroenterologists
in patients requiring frequent courses of corticosteroids
for ulcerative colitis. However, unlike in Crohn’s
disease, where there is good evidence that azathioprine
promotes both induction and maintenance of remis-
sion,30, 31 there are few such data in UC. Jewell and
Truelove’s study in 197432 randomized patients with
active colitis to standard therapy plus azathioprine or
dummy. They found no significant difference in remis-
sion rates at 1 month between the two groups, or even
at 1 year. However, when they split the patients into
those having their first attack of colitis and those having
a subsequent relapse, the relapse group were more likely
to be in remission at one year if taking azathioprine (this
almost reached statistical significance, P ¼ 0.055). Two
other subsequent studies 33, 34 showed that azathio-
prine had a steroid-sparing effect but that it did not alter
the clinical or inflammatory course of the disease.
Hawthorne et al. examined azathioprine in UC from a
different angle.35 In a double-blind, placebo-controlled
study they randomized outpatients with stable disease
on azathioprine for at least 6 months to stop the drug or
continue. The relapse rate in the group that stopped
azathioprine was significantly higher than in the group
that continued the drug. In further favour of a benefit of
azathioprine was the median dose which was only
100 mg, implying that probably at least half the group
were on <2 mg/kg body weight, and that the benefits of
azathioprine may be even greater than they found. For
these various reasons it is not possible to calculate
meaningful NNTs.
Ciclosporin
Ciclosporin is the latest commonly used treatment in the
management of (severe) ulcerative colitis. There is only
one placebo-controlled trial,36 with small patient num-
bers, which gave impressive response rates (Table 4). It
would be unethical to expect further placebo-controlled
trials in this situation given the known high mortality of
untreated severe colitis, and the recognized benefits of
corticosteroids. Therefore our ‘best guess’ for the expec-
ted response rates to ciclosporin is based on nonplacebo-
controlled data, which gives short-term response rates of
64–83%,37–39 similar to the original paper.
Table 3. Studies of 5-ASA preparations vs. placebo in maintenance of remission of ulcerative colitis
Study Drug Follow-up
Placebo maintenance
of remission rate (%)
Drug maintenance of
remission rate (%)
Number needed to
treat (95% CI)
Misiewicz 196522 Sulfasalazine 2 g 1 year 8/38 (21) 24/42 (57) 3
Dissanayake 197323 Sulfasalazine 2 g 6 months 14/31 (45) 29/33 (88) 2
Riis 197324 Sulfasalazine variable dose 6 months 17/24 (71) 19/25 (76) 20
Sandberg 198625 Olsalazine 1 g 6 months 27/49 (55) 40/52 (77) 5
Wright 199326 Olsalazine 2 g 1 year 16/52 (31) 18/49 (37) 17
Miner 199527 Pentasa 4 g 1 year 34/102 (33) 59/103 (57) 4
Hanauer 199628 Asacol 6 months 25/87 (29)
0.8 g 40/90 (44) 6
1.6 g 38/87 (44) 7
Hawkey 199729 Mesalazine 1.6 g 6 months 45/111 (41) 59/99 (60) 5
Overall 186/494 (38) 326/580 (56) 6 (4–8)
Sulfasalazine 39/93 (43) 72/100 (72) 3 (2–6)
Other 5-ASA 147/401 (37) 254/480 (53) 6 (4–10)
Table 4. Study of ciclosporin vs. placebo in the treatment of ulcerative colitis
Study Drug Follow-up
Placebo remission
rate
Drug remission
rate
Number needed to
treat (95% CI)
Lichtiger 199436 Ciclosporin 4 mg/kg per day i.v. 7 days 0/9 (0%) 9/11 (82%) 1.2 (1–2.5)
146 J. R. BEBB & B. B. SCOTT
� 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20, 143–149
DISCUSSION
Our aim when writing this review was to provide
information on expected benefits of commonly used
drugs in ulcerative colitis over placebo or no treatment.
Our findings are summarized in Table 5, which could be
useful as reference in the outpatient clinic.
In the outpatient management of flares of ulcerative
colitis corticosteroids are effective in 65% or more of
patients. 5-ASA compounds are less effective, associated
with a remission induction of only 20% and with an
NNT of 10 (95% CI 7–21). They seem to be more
effective if the daily dose is 3 g or greater (NNT ¼ 8;
95% CI 5–20). Sulfasalazine, although used for the
longest time, has not been subjected to placebo-
controlled trials of remission induction. However, it
seems to be as effective as the other 5-ASA compounds
with which it has been compared in controlled trials.
5-ASA compounds are of greater, although still limited,
effectiveness in maintenance therapy with an NNT of 6
(95% CI 4–8). There is evidence suggesting a benefit of
azathioprine in maintenance of UC and it has an
additional steroid-sparing effect.
In the inpatient management of severe attacks of
ulcerative colitis, i.v. fluids and corticosteroids are
associated with remission in up to three-quarters of
patients. Untreated severe attacks are associated with
high mortality. Ciclosporin is a useful drug in those that
have failed to improve on i.v. corticosteroids and
induces short-term remission in up to 80% of patients.
As a result of this analysis, we would offer steroids to
patients severely or moderately ill with active UC.
If only mildly ill, we would first offer a 5-ASA
preparation in high dosage (‡3 g daily) but change
to steroids within a few weeks if there is no substantial
improvement. When in remission, we would offer
continued treatment with a 5-ASA preparation in the
recommended doses, but would readily agree to stop it
if a patient with distal disease felt it was not helpful –
they would probably be correct. For patients with more
extensive disease, who have an increased risk of colon
cancer, we would encourage long term 5-ASA use
because of the probable additional benefit of cancer
prevention .40 If there is relapse within a year we
would give a further course of steroids and start
azathioprine (and continue long term if tolerated and
effective). If the disease remains active we would try
to achieve remission by inpatient treatment with
i.v. steroids and/or ciclosporin.
While we do not include it within this review, it is
important to bear in mind that surgery remains an
important management option in both the acute
situation and chronic refractory ulcerative colitis, and
in expert hands can yield excellent results.
We have concentrated on placebo-controlled trials in
this review so as to be able to advise patients of the
benefits a treatment can offer them over no treatment.
We accept that, for new treatments being developed, it
may not be possible to conduct placebo-controlled trials,
particularly in the acute setting with its high associated
morbidity and mortality. We also accept that our review
has limitations and could be criticized for having
amalgamated trials with slightly different groups of
patients, often on slightly different doses of similar drugs
(especially in the case of the 5-ASA compounds).
However, for the purpose of informing patients and
doctors of likely benefit, such approximation is consid-
ered acceptable.
Table 5. Summary of expected placebo and drug induced remission/maintenance of remission rates in ulcerative colitis
Drug
Induction of remission
or maintenance
Placebo response
rate %
Drug response
rate %
Number needed to
treat (95% CI)
Prednisone in mild disease Induction of remission 17 68 2 (1.4–5)
Prednisolone in mild to
moderate disease
Induction of remission – 65 –
Hydrocortisone i.v. in
severe disease
Induction of remission – 60–73 –
5-ASA Induction of remission 10 20 10 (7–21)
5-ASA Induction of remission
or improvement
35 59 4 (3–5)
5-ASA Maintenance 37 53 6 (4–8)
Ciclosporin Induction of remission 0 82 1.2 (1–2.5)
Ciclosporin Induction of remission
(nonplacebo controlled trials)
– 64–83 –
SYSTEMATIC REVIEW: DRUG EFFECTIVENESS IN ULCERATIVE COLITIS 147
� 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20, 143–149
This review also discloses the severe limitations of our
current tre