Journal of Crohn's and Colitis (2008) 2, 263268

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

SPECIAL ARTICLE

Historical evolution of the management of severe

ulcerative colitis
Renzo Caprilli a,, Valeria Clemente a , Giuseppe Frieri b
a
b

University of Rome La Sapienza, Rome, Italy

University of L'Aquila, L'Aquila, Italy

Received 13 March 2008; accepted 23 March 2008

KEYWORDS
Ulcerative;
Toxic megacolon;
Colectomy;
Corticosteroids;
Abdominal X-ray

Abstract
Ulcerative colitis was first described in 1859, but it was not until the early 20th century that it
became a well recognized clinical entity. The patients of the old series showed high mortality
rate ranging from 30% in the severe forms to 60% in the fulminating forms.
The introduction of corticosteroids in the 1950s dramatically improved the prognosis of patients
with severe ulcerative colitis. The strategy based on intensive medical treatment, early detection
of risk factors and early surgery progressively reduced the mortality rate to less than 1%.
Tachycardia, fever, reduced number of intestinal sounds, hypoalbuminaemia, hypokalaemia
metabolic alkalosis and elevated C-reactive protein were recognized to be the most useful risk
factors. Plain abdominal X-ray remains the very reliable suitable tool to detect early complications of severe colitis.
Once reduced the mortality near to zero, treatment has been addressed to avoid colectomy.
Cyclosporine and Infliximab are currently used as rescue therapy, however, despite the high
remission rates achieved with both drugs, about 50% of the treated patients ultimately will come
to colectomy over the next few years.
2008 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

1. Introduction
A patient with ulcerative colitis (UC) may present suddenly
severe symptoms as bloody diarrhoea, fever, tachycardia and
anaemia. Today such a patient risks to die only in rare and
complicated cases, but no more than 60 years ago his mor

Conference Presentation: 3rd Congress of ECCO, Lyon, France, 2008.

Corresponding author. Via di Novella, 11, 00199 Rome, Italy. Tel.: +39
06 86275827; fax: +39 06 86275506.
E-mail address: caprilli@interfree.it (R. Caprilli).

tality risk was expected to be up to 60%. This was the case of

Miss Banks, the first patient described to have a non infective dysentery by Samuel Wilks of London, in 1859. The
author defined this condition as a simple ulcerative colitis1
but it was not until the early 20th that UC became a well
recognized clinical entity, due to the introduction of the
electric sigmoidoscope and barium enema.2
Miss Banks, like other patients with UC, died as the
treatment at the early 20th century was empirical, anecdotical and inefficacious. Consequently, hemorrhage, peritonitis and sepsis were frequent complications of the disease and

1873-9946/$ - see front matter 2008 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.crohns.2008.03.008

264
ineluctable causes of death. Such outcome was the result of a
medical treatment mainly consisting of in bed rest, high
calory-protein, low residue diet, vitamin supplement and
blood transfusion. Also topical treatment was tried to ameliorate prognosis, but rectal instillations of various substances
such as hydrogen peroxide, silver nitrate, tannic acid, bismuth didn't modify the clinical course of the disease that was
invariably dangerous and disabling.3
The surgical approach to UC throughout the years has
varied considerably with the operative procedure in the early
1900s being appendicostomy, caecostomy and ileostomy.2
These procedures were associated with many technical problems and complications and didn't resolve patients' problems.
In the following years, the introduction of antibiotics and the
modification in the ileostomy procedure by Brooke5 dramatically improved the results of the operation. Surgery became
a curative procedure in the 1950s with the introduction of
total proctocolectomy with end ileostomy.6 During these
early years the reluctance to wear an uncomfortable bag led
patients to be referred for surgery very late and in a severely
debilitate state and prognosis was invariably poor. Therefore,
until 1950 the mortality for UC continued to be high with
reports of 75% in the Birmingham (UK) series in 19333 and 22%
in the Oxford (UK) series in 1950.4
The first drug really effective in the treatment of UC was
sulphasalazine, introduced in the 1940s7 but the true revolution in the treatment of the severe disease was the advent
of corticosteroids.

2. The cortisone period (19551990)

The cortisone period was characterized by the introduction
of intravenous corticosteroids, the early surgery and the
search for prognostic factors.

2.1. Intensive intravenous corticosteroid regimen

The introduction of steroid treatment dramatically improved
the prognosis of patients with severe UC. In 1955, Truelove and
Witts reported the results of the first controlled trial on the
treatment of UC, in which, following steroids, the mortality of
patients with severe UC, at the first attack, dropped to 7%,
compared with 24% in the placebo group, although patients
presenting with very severe attacks of UC were not included in
this study. They also observed a significant improvement in the
remission rate in the cortisone-treated group compared to the
control group (42% vs 13%).8 In 1974, Truelove and Jewell
reported the results of their uncontrolled experience in 49
patients submitted to a 5-day intensive regimen based on
intravenous steroids and early surgery for the treatment of the
most severe attacks of UC, showing a further reduction in the
mortality rate.9 This treatment, known as the Oxford regimen,
consisted in stopping oral alimentation except water, intravenous administration of 3 l of fluid per day with potassium and
vitamins B and C, blood transfusions, prednisolone-21-phosphate 60 mg (or hydrocortisone 400 mg), tetracycline 1 g.
Hydrocortisone 100 mg was administered via the rectum.
If no definite improvement was observed after 5 days of
intensive treatment surgery was recommended (early surgery).
The Oxford method was found to be very useful not only
because it was able to induce rapid remission, in many patients,

R. Caprilli et al.
but also because its failure proved to be a strong indication for
urgent surgery.

2.2. Early surgery

Early surgery was an innovation of the cortisone period. To
assess the validity of early surgery, Goligher from Leeds, in
1967, compared the outcome of a severe attack of UC in two
consecutive groups of patients.10 In the first (observed
between 1952 and 1963), the patients were treated with
corticosteroids and late surgery, in the second (observed between 1964 and 1966) with corticosteroids and early surgery.
The overall mortality rate in the two groups dropped from
11.3% to 1.3%. Surgery consisted of ileostomy with proctocolectomy or subtotal colectomy. These findings clearly
suggested that early surgery might present considerable advantages in those patients presenting a severe attack of UC
failing to respond rapidly to intensive medical treatment. The
clearcut reduction in mortality rate following the policy of an
intensive corticosteroid regimen, associated with early surgery, was confirmed by several other European studies.1113
The surgical procedures performed during that period
were proctocolectomy and ileostomy,6 subtotal colectomy
and ileo-rectal anastomosis14 and, after 1980, proctocolectomy and ileo-anal pouch anastomosis.15
Proctocolectomy combined with ileostomy (Brooke ileostomy, in particular), represented the standard operation for UC
for many years. The advantages of this procedure were that it
was simple to perform and removes all the diseased intestine.
The disadvantages were stoma, and ensuing urinary or sexual
dysfunction.
Subtotal colectomy with ileo-rectal anastomosis was rarely
performed, primarily because a large area of diseased mucosa
is left in situ. It was considered as an option in those patients
refusing ileostomy and in whom the disease involved a minimal
area of the rectum. Surveillance of the residual stump of the
rectum was mandatory to monitor the risk of cancer.
After 1980, proctocolectomy, with ileo-anal pouch anastomosis, became the operation of choice for most patients
with UC. The operation is attractive since it avoids a permanent ileostomy, cures the patient of the disease whilst
preserving ano-rectal function.
The most commonly observed short-term complications
are: small bowel obstruction, anastomotic stricture, pouch
leak and pelvic abscess. Long-term complications include small
bowel obstruction, pouch fistulae and pouchitis.16
Table 1

Prognostic factors in severe UC

Clinical-laboratory
Altered consciousness
Pulse N 120/min
Fever N 38 C
Intestinal sound b 5/min
Albumin b 3 g/100 ml
Ca++ b 4.0 mEq/l
Cl b 95
K+ b 2.5
HCO3 N 32
pH N 7.50
CRP N 45 mg/l

Jalan, 1969

Lennard-Jones, 1975

Caprilli, 1976
Travis, 1996

Historical evolution of the management of severe UC

Table 2

Plain abdominal X-ray

Small bowel distension (Impending

megacolon)
Mucosal islands
Colonic dilatation
Colonic deep ulcerations

Caprilli, 1976

Lennard-Jones,
1975
Lennard-Jones,
1975

2.3. Search for prognostic factors

The key prognostic factors most commonly used to predict
the outcome of severe UC can be classified as clinical, laboratory, radiologic and endoscopic features.17

2.4. Clinical and laboratory features

In the very early studies,1820 impaired consciousness and
lethargy, related to toxicity, were considered to be signs of
extremely severe disease (Table 1). Since treatment has
meanwhile improved, these symptoms are now rarely found
but, when present, are usually representative of an extremely
severe condition, indicating the ongoing development of the
so-called multiple organ dysfunction syndrome (MODs).21 In
these patients mortality continues to be very high.
Tachycardia, high fever, reduced number of intestinal
sounds, and hypoalbuminaemia were reported by LennardJones to be factors indicative of poor prognosis.22
Patients with severe UC often present metabolic alkalosis.23 It has been shown that arterial blood pH rises progressively with increased severity of UC and as the lesions

265
become more widespread.23 High blood pH and high bicarbonate concentration, together with low serum potassium
chloride and calcium levels, have been associated with fatal
outcome in toxic megacolon complicating UC.24
A C-reactive protein (CRP) concentration N 45 mg/l on the
third day of intensive medical treatment, in patients continuing to present diarrhoea (N3 bowel movements per day), was
found to be associated with an 85% risk of colectomy.25
Evaluation of the full blood count, CRP concentration,
serum electrolytes, acidbase balance, as well as serum albumin concentration should be performed every 2448 h. Daily
monitoring of stool frequency, consistency, amount of blood,
pulse rate and temperature is also mandatory.

2.5. Radiologic features

In patients with an acute attack of severe UC, daily abdominal X-rays, taken in the supine and erect position, provide very useful diagnostic features (Table 2).
Increased small bowel gas, and occasional distension of the
stomach, is a frequent finding on plain abdominal X-ray film,
being present in approximately 50% of patients with severe
colitis.13,26 The finding of persistent small bowel distension on
plain abdominal X-ray film characterizes a subgroup of
patients at high risk for the development of toxic megacolon,
and indicates that they have a condition that we have called
impending megacolon13,23,24 (Fig. 1). The early detection of
impending megacolon is very important, in clinical practice, as
it has been shown in a prospective study on patients with
severe UC in which, mortality due to toxic megacolon was zero
when megacolon was preceded by intestinal distension and
intensive therapy was promptly started.13

Figure 1 Impending megacolon evolving to toxic megacolon. Plain abdominal film of the abdomen in supine position in a patient with
severe UC. On the left, gaseous distension of the small bowel (impending megacolon), with initial segmental distension of the transverse
colon. On the right, two days later diffuse dilatation of the colon and the small bowel (overt toxic megacolon).

266
The pathogenesis of distension of the stomach and of the
small bowel in patients with severe UC still remains to be fully
elucidated. Pathophysiologic and experimental data suggest
that distension results from the activation of extrinsic intestinointestinal inhibitory reflexes, which induce paralytic ileus.27
Toxic megacolon is defined as total or segmental nonobstructive hypotonic dilatation of the colon, classically exceeding 5.5 cm in diameter, in the transverse colon, on plain
abdominal X-ray film,28 with or without signs of systemic
toxicity. Again, pathogenesis of toxic megacolon also remains
to be fully elucidated. The most convincing explanation for
colonic dilation appears to be the excessive local production of
soluble inflammatory mediators with inhibitory effects on
colonic muscle tone. Nitric oxide, which is considered to be the
most important non adrenergic, noncholinergic neurotransmitter in the gut, might play a key role.2931
Abdominal X-ray can also be used to detect deep colonic
ulcerations (Fig. 2) and abnormalities of the colonic mucosa.32

2.6. Endoscopic features

Endoscopy is effective in revealing severe mucosal lesions
which usually extend from the rectum to the caecum. Severe
disease is characterized by ulcers and spontaneous bleeding.33
Deep colonic ulcerations, detected at endoscopy, are well
correlated with the depth of ulcerations found in colectomy
specimens, features predictive of complications, and associated
with a higher rate of colectomy.22,32,33 Although sigmoidoscopy
without air insufflations, is safe in experienced hands, several
authors question the safety and usefulness of this examination in

Figure 2 Deep colonic ulcerations. Plain abdominal film of the

abdomen in supine position in a patient with severe UC. Diffuse
intestinal distension. Presence of deep ulcerations in the sigmoid
(arrows).

R. Caprilli et al.
acute severe colitis.33 Total colonoscopy, such as double contrast
enema, should be avoided due to the risk of complications (toxic
megacolon, perforation and massive bleeding).
Rectal biopsy is important to confirm the diagnosis of UC
and to exclude infective colitis.
In conclusion, the policy adopted in the cortisone period
consisting of intensive intravenous corticosteroid regimen in
association with early surgery and early detection of risk
factors has proved to be successful in reverting the course of
the disease towards fulminating colitis and in reducing the
overall mortality to almost zero.
However, about 3040 of patients with severe UC
continue to need colectomy after failure of corticosteroid
therapy, both in adults and children.34,35

3. Rescue therapy period (19902007)

Once reduced the mortality for severe UC near to zero, over
the past 15 years, many attempts have been made to avoid
surgery since colectomy has not only a negative effect on
quality of life, but also a high peri-operative morbidity and
mortality36 and, moreover, involves high costs.37 Treatment
attempted to avoid surgery after failure of intravenous steroids
is commonly defined as rescue therapy. Two main rescue
therapy strategies have so far been extensively studied (Cyclosporine and Infliximab) but others (Visilizumab, Tacrolimus,
Leukocytapheresis) are also under investigation.

3.1. Cyclosporine
The use of intravenous (i.v.) Cyclosporine (CyC) in the
management of severe UC resulted from a North American
placebo-controlled randomised trial, published in 1994, that
reported the efficacy of 4 mg/Kg of Cyc i.v. administered to
patients not responding to intravenous glucocorticosteroids.38
After some years a European double-blind controlled trial
showed that CyC alone is at least as effective as corticosteroids
in the treatment of patients with severe UC.39 The same group
also performed a randomised, double-blind study comparing
4 mg/kg day with 2 mg/kg day i.v. CyC. The study showed that
high-dose CyC has no additional clinical benefit over low-dose
CyC in the treatment of severe attacks of UC. Although differences in adverse events were not observed in the short
term, it was concluded that as most Cyc-associated adverse
events are dose dependent, the use of 2 mg/kg should improve
the long-term toxicity profile of the agent.40
A frequency N8 stools per day or CRP N 45 mg/l at day 3 has been
demonstrated to predict the need for colectomy.25 If remission is
achieved with CyC i.v., oral CyC is continued for 36 months.
The long-term outcome in a large series of patients
treated with CyC for severe colitis refractory to intravenous
steroids was recently reported. After 3 years, 90% of patients
had relapsed; after 7 years 58% of patients had undergone
colectomy. Long-term prognosis is reported to be improved
by the introduction of azathioprine or mercaptopurine upon
discharge from the hospital in association with oral CyC as
bridge therapy.41
Following 12 years experience a Belgian group reported
that CyC is an effective short- to medium-term treatment for
patients with severe UC but at 7 years, 88% of patients will
require colectomy.42

Historical evolution of the management of severe UC

Very recently, CyC i.v. has been used as topdown
monotherapy in severe UC. This strategy was found to be superior
to the conventional step-up approach (CsA in patients who
failed to respond to iv Steroids) in avoiding colectomy.43
A recent Cochrane review of the literature on severe UC
including only randomised clinical trials comparing CyC with
placebo or no intervention showed that the evidence
indicating that CyC is more effective than standard corticosteroid therapy is weak and Cyc does not avoid the overall
need for colectomy.44 The drawback of this review is that
only two randomised controlled trials have been included.
Concerns about toxicity have also prevented the widespread use of Cyc in many hospitals. Cyc can be associated
with severe side-effects (e.g. hypertension, renal failure,
neurotoxicity, hepatotoxicity, diabetes and hypertrichosis),
which lead to death in a significant minority of patients, thus
limiting its use. Adverse effects are less frequent with the
lower 2 mg/kg/day dose. The benefits of avoiding colectomy
should, therefore, always be balanced against the risk of
inducing profound immunosuppression and severe sideeffects. Furthermore, in many instances, administration of
CyC only delays but does not prevent colectomy.
Very recently a Meta-Regression performed on 32 studies for
a total of 1991 patients showed that the short-term colectomy
rate, in severe UC, had remained stable over the last 30 years
despite the introduction of CyC. In the pooled analysis, the
mean colectomy rate was 27% and mortality of 1%.45

3.2. Infliximab
Monoclonal anti-tumour necrosis factor antibodies (i.e.
Infliximab) have now been used to treat severe UC. However,
most of the published studies are uncontrolled, include a
small number of patients and show controversial results. The
first randomised controlled trial on Infliximab for UC did not
support its use in the management of moderately active
glucocorticoid-resistant UC; however patients with severe
disease were specifically excluded from the study.46
Since then, data from two randomised controlled clinical
trials (ACT1 and ACT2), which included over 700 patients with
moderate-to-severe UC, have been published in a single
article.47 Infliximab, given i.v. at the dose of 5 mg/kg, at 0,
2 and 6 weeks, was effective at inducing clinical remission,
healing the lesions and demonstrating a steroid-sparing effect.
It was not clear, however, how many patients included in these
trials had really severe UC requiring hospital admission with an
intensive treatment regimen.
A Scandinavian placebo-controlled trial has recently shown
that Infliximab given as a single 5 mg/kg infusion was significantly more effective than placebo in avoiding colectomy,
at 3 months, in patients with severe UC refractory to corticosteroids.48 The results of this study at 2-year follow-up also
showed a statistically lower colectomy rate in the Infliximab
group (46% vs 76%; P b 0.05).49 These results were confirmed by
a pan-Scotland retrospective audit on 39 patients with severe
UC showing that 66.6% of patients avoided urgent colectomy
following Infliximab rescue therapy.50 Similar results were
observed by a Spanish multicentre retrospective survey including 47 UC patients, either steroid resistant or dependent.51
In the Oxford experience, 85% of the patients receiving
Infliximab as rescue therapy for severe UC, avoided early
colectomy, but overall 57% of these patients ultimately un-

267
derwent colectomy after a median period of 3 months since
their last infusion.52
In the experience of the Leuven group, 19% of patients
treated with Infliximab for moderate-severe UC, followed
for a median time of 2.5 years needed colectomy.53
In summary, the use of Infliximab in the treatment for
severe UC seems promising, even if its role still remains to be
clearly defined. In a recent systematic review on Infliximab
therapy in UC including 34 studies for a total of 896 patients,
only 207 patients had severe disease.54 In particular, whether
the early use of Infliximab will prevent colectomy is uncertain.
Uncontrolled studies suggest that Infliximab used as rescue
therapy, like CyC, is effective only in delaying the need of
colectomy since N50% of treated patients require surgery over
57 years. The better safety profile and the simplicity of
Infliximab versus CyC suggest that Infliximab is the best
alternative to surgery in steroid-refractory severe UC.

4. Final considerations
The advent of corticosteroids in the 1950s with the application
of the intensive regimen, early detection of risk factors, early
surgery and strict collaboration between gastroenterologist
and surgeon dramatically reduced the mortality rate in severe
UC in the last decades.
Once mortality was reduced near to 0% gastroenterologists changed the primary outcome of treatment seeking to
avoid colectomy and possibly heal the mucosal lesions. Currently, two drugs are used to avoid surgery in severe UC:
Cyclosporine and Infliximab. However, despite high remission rates achieved with both Cyclosporine and Infliximab,
about 50% of the treated patients ultimately will come to
colectomy over the next few years. The need for new, safer
and more effective drugs in the medical therapy of severe
UC is therefore pressing.

Acknowledgements
Declaration of funding interests: none
The authors thank Mrs. Marian Shields for her help in
reviewing the English manuscript.
All authors conceived of the study, and participated in its
design and coordination and helped to draft the manuscript.
All authors read and approved the final manuscript.

References
1. Wilks S. The morbid appearance of the intestine of Miss Banks.
Med Times Gaz 1859;2:64. Quoted from: Crohn BB. An historic note on ulcerative colitis. Gastroenterology 1859;42:
366369.
2. Kirsner JB. Origins and directions of inflammatory bowel disease.
Dardrecth Kluwer Academic Publisher; 2001.
3. Hardy TL, Bulmer E. Ulcerative colitis: survey of 95 cases. Br Med
J 1933;ii:812813.
4. Rice-Oxley JM, Truelove SC. Ulcerative colitis: course and prognosis. Lancet 1950;i:663666.
5. Brooke BN. The management of an ileostomy including its complications. Lancet 1952;2:102104.
6. Dennis C. Ileostomy and colectomy in chronic ulcerative colitis.
Surgery 1945;18:435452.

268
7. Svartz N. Salazopyrin: a new sulfonamide preparation. A
Therapeutic results in rheumatoid arthritis. B Therapeutic results
in ulcerative colitis. C Toxic manifestations on treatment with
sulfanilamide preparations. Acta Med Scand 1942;110:577590.
8. Truelove SC, Witts LJ. Cortisone in ulcerative colitis: final report
on a therapeutic trial. Br Med J 1955;ii:10411048.
9. Truelove SC, Jewell DP. Intensive intravenous regimen for severe
attacks of ulcerative colitis. Lancet 1974;1:10671070.
10. Goligher JC, de Dombal FT, Graham NG, Watkinson G. Early
surgery in the management of severe ulcerative colitis. Br Med J
1967;3:193195.
11. Truelove SC, Willoughby CP, Lee EG, et al. Further experience in
the treatment of severe attacks of ulcerative colitis. The Lancet
1978;2:10861088.
12. Jarnerot G, Ralny P, Sandberg Gertzen H. Intensive intravenous
treatment of ulcerative colitis. Gastroenterology 1985;89:10051013.
13. Caprilli R, Vernia P, Latella G, Torsoli A. Early recognition of
toxic megacolon. J Clin Gastroenterol 1987;9:160164.
14. Aylett S. Total colectomy and ileo-rectal anastomosis in diffuse
ulcerative colitis. Br Med J March 1957;2:489492.
15. Parks AG, Nicholls RJ, Bliveau P. Proctocolectomy without
ileostomy for ulcerative colitis. BMJ 1978;2:8588.
16. Cohen JL, Strong SA, Hyman NH, et al. Practice parameters for
the surgical treatment of ulcerative colitis. Dis Colon Rectum
2005;48:19972009.
17. Caprilli R, Viscido A, Latella G. Review. Current management of
severe ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol
2007;4:92101.
18. Gallagher ND, Goulston SJM, Wyndham N, et al. The management of fulminant ulcerative colitis. Gut 1962;3:306.
19. Jalan KN, Sircus W, Card WI, et al. An experience of ulcerative
colitis. Gastroenterology 1969;57:6882.
20. Zer M, Wolloch Y, Ditnsman M. Pitfalls in the surgical management of
fulminating ulcerative colitis. Dis Colon Rectum 1972;15:280287.
21. Caprilli R, Latella G, Vernia P, Frieri G. Multiple organ dysfunction in ulcerative colitis. Am J Gastroenterol 2000;95:
12581262.
22. Lennard-Jones JE, Ritchie JK, Hilder W, et al. Assessment of
severity in colitis: a preliminary study. Gut 1975;16:579584.
23. Caprilli R, Vernia P, Colaneri O, Torsoli A. Blood pH: a test for
assessment of severity on proctocolitis. Gut 1976;17:763769.
24. Caprilli R, Vernia P, Colaneri O, Frieri G. Risk factors in toxic
megacolon. Dig Dis Sci 1980;25:817822.
25. Travis SPL, Farrant JM, Ricketts C, et al. Predicting outcome in
severe ulcerative colitis. Gut 1996;38:905910.
26. Chew CN. Small bowel gas in severe ulcerative colitis. Gut
1991;32:15351537.
27. Caprilli R, Onori L. Pathogenesis of gastrointestinal distension in severe
ulcerative colitis: a hypothesis. Gastroenterol Int 1992;5:268272.
28. Hywel Jones J, Chapman M. Definition of megacolon in colitis.
Gut 1969;10:562564.
29. Mourelle M, Casellas F, Guarner F, et al. Induction of nitric oxide
synthase in colonic smooth muscle from patients with toxic
megacolon. Gastroenterology 1995;109:14971502.
30. Latella G, Vernia P, Viscido A, et al. GI distension in severe
ulcerative colitis. Am J Gastroenterol 2002;97:11691175.
31. Onori L, Aggio A, D'Al S, et al. Role of nitric oxide in the impairment
of circular muscle contractility of distended, uninflamed mid-colon
in TNBS-induced acute distal colitis in rats. World J Gastroenterol
2005;11:56775684.
32. Buckell NA, Williams GT, Bartram CI, et al. Depth of ulceration in
acute colitis. Correlation with outcome and clinical and radiological features. Gastroenterology 1980;79:1925.
33. Carbonnel F, Lavergne A, Lemann M, et al. Colonoscopy of acute
colitis. A safe and reliable tool for assessment of severity. Dig
Dis Sci 1994;39:15501557.

R. Caprilli et al.
34. Carter MJ, Lobo AJ, Travis SPL. Guidelines for the management
of inflammatory bowel disease in adults. Gut 2004;53(suppl V):
V1V16.
35. Turner D, Walsh CM, Benchimo EL, et al. Severe paediatric
ulcerative colitis: incidence outcomes and optical timing for
second-line therapy. Gut 2008;57:331338.
36. Travis S. Review article: saving the colon in severe colitis the
case for medical therapy. Aliment Pharmacol Ther 2006;24
(suppl 3):6873.
37. Kaplan GG, Mccarthy EP, Ayanian JZ, et al. Mortality, morbidity,
and costs associated with colectomies in ulcerative colitis
patients in the US. Gastroenterology 2007;132(suppl 2):a-654.
38. Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in
severe ulcerative colitis refractory to steroid therapy. N Engl J
Med 1994;330:18411845.
39. D'Haens G, Lemmens L, Geboes K, et al. Intravenous cyclosporine
versus intravenous corticosteroids as single therapy for severe attacks
of ulcerative colitis. Gastroenterology 2001;120:13231329.
40. Van Assche G, D'Haens G, Noman M, et al. Randomized double-blind
comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in
severe ulcerative colitis. Gastroenterology 2003;125:10251031.
41. Campbell S, Travis SPL, Jewell DP. Cyclosporine use in acute
ulcerative colitis: a long term experience. Eur J Gastroenterol
Hepatol 2005;17:7984.
42. Moskovitz DN, Van Asche G, Maenhout B, et al. Incidence of
colectomy during long term follow-up after cyclosporine induced remission of severe ulcerative colitis. Clin Gastroenterol
Hepatol 2006;4:760765.
43. Yoshimura N, Suzuki Y, Takazoe M. Clinical efficacy of topdown
intravenous cyclosporine therapy in patients with severe ulcerative colitis. Gastroenterology 2007;132:A-182.
44. Shibolet O, Regushevskaya E, Brezis M, et al. Cyclosporine-A for
induction of remission in severe ulcerative colitis. Cochrane
Database Syst Rev 2005;1 Art. No CD004277.
45. Turner D, Walsh CM, Steinhart AH, Griffiths AM. Response to
corticosteroids in severe ulcerative colitis: a systematic review of
the literature and a meta-regression. Clin Gastroenterol Hepatol
2007;5:103110.
46. Proberts CS, Hearing SD, Schreiber S, et al. Infliximab in
moderately severe glucocorticoid resistant ulcerative colitis: a
randomized controlled trial. Gut 2003;52:9981002.
47. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for
induction and maintenance therapy for ulcerative colitis. N Engl
J Med 2005;353:24622476.
48. Jarnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescue therapy
in severe to moderately severe ulcerative colitis: a randomized
placebo-controlled study. Gastroenterology 2005;128:18051811.
49. Gustavsson A, Jarnerot G, Hertervig E, et al. A 2-year follow-up of
the SwedishDanish infliximab/placebo trial in steroid resistant
acute ulcerative colitis. Gastroenterology 2007;132:A-146.
50. Lees G, Heys D, Shand AG. Infliximab as rescue therapy in acute
severe UC: a survey of the Scottish Society of Gastroenterology
(Ssg). Gastroenterology 2007;132:A-181.
51. Gonzales-Lama Y, Fernandez-Blanco I, Lopez-SanRoman A, et al.
Open-label infliximab therapy in ulcerative colitis: a multicenter
survey of results and predictors of response. Gastroenterology
2007;132:A-186.
52. Jakobovits SL, Jewell DP, Travis SPL. Infliximab for the
treatment of ulcerative colitis: outcome in Oxford from 2000
to 2006. Aliment Pharmacol Ther 2007;25:10551060.
53. Ferrante M, Vermeire S, Noman M, et al. Colectomy rates after
infliximab for refractory ulcerative colitis and predictive
factors. Gastroenterology 2007;132(suppl 2):A-144.
54. Gisbert JP, Gonzalez-Lama Y, Mat J. Systematic review:
infliximab therapy in ulcerative colitis. Aliment Pharmacol
Ther 2006;25:1937.