Current management of severe ulcerative colitis - Nature

REVIEW www.nature.com/clinicalpractice/gasthep

Current management of severe ulcerative colitis Renzo Caprilli*, Angelo Viscido and Giovanni Latella

S U M M A RY Approximately 15% of patients with ulcerative colitis develop an acute attack of severe colitis, and 30% of these patients require colectomy. Severe ulcerative colitis is therefore considered a medical emergency, the management of which requires close collaboration between gastroenterologists and surgeons. The mortality rate for patients with severe ulcerative colitis is now 120 beats per minute

Lennard-Jones 197519

Fever >38 °C

Lennard-Jones 197519

Intestinal sounds 32 mmol/l)

Caprilli 1975–198020–22

Electrolyte imbalance (Ca2+ 3 bowel movements per day), is associated with an 85% risk of colectomy.25 Evaluation of the full blood count, CRP concentration, serum electrolytes, acid-base balance, and serum albumin concentration should be performed every 24–48 hours. It has also been shown that some genetic factors such as HLA-DRB1*0103 and the multidrug

NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY 93


A

B

Figure 1 Plain abdominal X-ray films of a patient with severe colitis. Both images were taken in the supine position and come from the author’s personal series of images. (A) Day 1: gaseous distension of several small bowel loops, which is indicative of impending megacolon. (B) Day 2: 24 hours later there is a typical picture of toxic megacolon (distension of transverse colon exceeding 6 cm).

resistance gene (ABCB1) can influence the course of ulcerative colitis, and in particular the need of colectomy for failed medical therapy. These genetic features, however, are not commonly used in clinical practice.18,26,27 Radiologic features

In patients with severe ulcerative colitis, daily abdominal X-rays taken in the supine and erect position are appropriate for the detection of small-intestine distension (‘impending megacolon’), colonic dilatation (toxic megacolon), and deep colonic ulcerations.24 Increased amounts of small-bowel gas, and occasionally distension of the stomach, is a frequent finding on the plain abdominal X-ray film of patients with toxic megacolon, but is also present in some 50% of patients with severe colitis.28 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 known as ‘impending megacolon’ (Figure 1).22,28,29 The early detection of impending megacolon is important in clinical practice. In a prospective study of patients with severe ulcerative colitis, mortality due to toxic megacolon was zero when megacolon was preceded by intestinal distension and intensive therapy was promptly started.28 The pathogenesis of distension of the stomach and of the small bowel in patients with severe ulcerative colitis is poorly understood, because

94 NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY

these segments are not affected by the inflammatory process. Pathophysiologic and experimental data suggest that distension can result from the activation of extrinsic intestine-intestinal inhibitory reflexes, which induce paralytic ileus.30 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,31 with or without signs of systemic toxicity. The pathogenesis of toxic megacolon remains to be fully elucidated. The most convincing explanation for colonic dilation seems to be the excessive local production of soluble inflammatory mediators that have inhibitory effects on colonic muscle tone. Nitric oxide, which is considered to be the most important nonadrenergic, noncholinergic neurotransmitter in the gut, might have a key role.30,32–34 Abdominal X-ray can also detect deep colonic ulcerations and abnormalities of the colonic mucosa. Endoscopic features

Endoscopy shows severe mucosal lesions usually extended from the rectum to the cecum. Severe disease is marked by ulcers and spontaneous bleeding.35 Deep colonic ulcerations detected by endoscopy are well correlated with the depth of ulcerations seen in colectomy specimens, features predictive of complications, and are associated with a higher rate of colectomy (Table 1).21,35–37 Although sigmoidoscopy without air insufflation is safe in experienced hands, several authors question the safety and usefulness of this examination in acute severe colitis.35 Total colonoscopy, as with double contrast enema, should be avoided because of the risk of complications (toxic megacolon, perforation and massive bleeding). Rectal biopsy is important to confirm the diagnosis of ulcerative colitis and to exclude infective colitis. Activity indices

Activity indices are mainly used in clinical trials. Two kinds of indices are used: invasive indices incorporating an endoscopic score, and noninvasive indices that do not require endoscopy for calculation (Table 2). Many indices of both kinds have been developed, but none have been clearly validated, and there is no gold standard. The first index is represented by the Truelove and Witts criteria based on symptoms, signs

CAPRILLI ET AL. FEBRUARY 2007 VOL 4 NO 2


Table 2 Clinical activity indices for ulcerative colitis. Parameter

Index Truelove– Witts 1955 Oxford

Powell-Tuck 1978 St Marks’ Hospital

Schroeder 1987 Mayo Clinic

Sutherland 1987 Calgary

Rachmilevitz 1989 Tel Aviv

Seo 1992 Fukuoka

Walmsley 1998 London

Score range

Mild–severe

0–24

0–12

0–12

0–29

70–300

0–20

Bowel frequency

X

X

X

X

X

X

X

Urgency

–

–

–

–

–

–

X

Stool consistency

–

X

–

–

–

–

–

Blood in stools

X

X

X

X

X

X

X

Abdominal pain

–

X

–

–

X

–

–

General well-being

–

X

–

X

–

–

X

Anorexia

–

X

–

–

–

–

–

Nausea/vomiting

–

X

–

–

–

–

–

Extraintestinal signs

–

X

–

–

X

–

X

Abdominal tenderness

–

X

–

–

–

–

–

Fever

X

X

–

–

X

–

–

Tachycardia

X

–

–

–

–

X

–

Anemia

X

–

–

–

X

X

–

Erythrocyte sedimentation rate

X

–

–

–

X

X

–

Physician’s global assessment

–

–

X

–

X

–

–

Sigmoidoscopy

–

X

X

X

–

–

–

and physician assessment.8 Powell-Tuck et al. subsequently developed an index (commonly called the St Mark’s index or the Powell-Tuck index) that also included endoscopic findings. It includes eleven items and is, therefore, often difficult to apply.38 The Mayo score, also called ulcerative colitis symptom score (UCSS) or clinical activity index (CAI), considers four features: stool frequency, rectal bleeding, findings at endoscopy, and physician’s global assessment. Each feature is scored on a scale of 0–3, with the overall score ranging from 0–12. Higher scores indicate more-severe disease.38 The ulcerative colitis disease activity index (UCDAI), similarly to the Mayo score, represents a simplified index specifically developed for clinical trials. It includes three clinical noninvasive items and an endoscopic item.38 The Seo index is a nonendoscopic activity index derived by regression model analysis. It is expressed as a calculation: (60× the number of bloody stools) + (13× the number of bowel movements) + (0.5× the erythrocyte

FEBRUARY 2007 VOL 4 NO 2 CAPRILLI ET AL.

sedi mentation rate) – (4× Hb concentration) – (15× albumin concentration) + 200. Values >220 correspond to severe disease according to the Truelove and Witt classification. Elevated scores correlate well with endoscopic activity and future need for colectomy.39 The Rachmilewitz score is a nonendoscopic numerical index that has been used in clinical trials.38 The simple clinical colitis activity index (SCCAI or simple index) is a non endoscopic score based on symptoms including six items.40 The disease activity index (DAI) accounts for stool frequency, rectal bleeding, and the physician’s rating. The DAI is the sum of the three component scores (each component from 0 to 3), with a maximum score of 9. Scores from 7 to 9 indicate severe disease. The DAI is essentially derived from the UCDAI excluding the endoscopic item.41 The fulminant colitis index is also expressed as a calculation: number of bowel movements/day + (0.94 × CRP >8 mg/l). Patients with a fulminant colitis index ≥8 have a high risk of undergoing colectomy.42



Intravenous steroids (5–7 days)

Response

Oral steroids

Stop oral feeding Total parenteral nutrition Hydrocortisone (100 mg four times daily) (Antibiotics)

No response

Intravenous ciclosproin

Surgery

Infliximab

Figure 2 Clinical algorithm for the management of uncomplicated severe ulcerative colitis adopted at the GI Unit, University of Rome “La Sapienza”. The patient is first admitted for intensive intravenous steroid therapy according to the ‘Oxford regimen’. If no clear-cut response is observed after 5–7 days of the intensive regimen, there are three treatment options available: intravenous ciclosporin, infliximab, or colectomy. Surgery is mandatory just a short time after the failure of ciclosporin or infliximab. Patients responding to intensive therapy are switched to oral steroids.

Statistical comparison between invasive and noninvasive indices showed that endoscopy items add little additional information to activity indices, probably because endoscopy items in the invasive indices correlate well with clinical items such as bleeding and stool frequency. The clinical practice of treating patients based on reported symptoms is therefore appropriate.43 MEDICAL TREATMENT Uncomplicated severe ulcerative colitis

Steroids The Oxford regimen for the treatment of severe ulcerative colitis is essentially based on the use of intravenous corticosteroids, the meticulous monitoring of patients and clear decision making concerning surgery (Figure 2). The regimen also consists of immediate hospital admission, the halting of oral feeding (with subsequent bowel rest), adequate fluid intake and electrolyte replacement, intravenous nutrition, correction of hypoalbuminemia and anemia, intravenous antibiotics, and rectally administered corticosteroids. It was reported that 75% of patients who had a severe attack of ulcerative colitis responded to this therapy (60% had a complete response and 15% showed improvement).9 The lack of marked improvement by the end of day 5 of this intensive therapy was considered an absolute indication for emergency colectomy.9,44 These results were later confirmed in the US.45 The corticosteroid-based regimen for severe ulcerative colitis has never been validated by controlled clinical trials.


Corticosteroids can be given at a daily dose of 60–80 mg methylprednisolone or 400 mg hydrocortisone, administered intravenously. Studies conducted to compare different types of steroids and adrenocorticotropic hormone did not demonstrate any clear advantage of one type with respect to the others.46–48 Adrenocorticotropic hormone, however, seemed somewhat more effective in patients who had not received prior steroid therapy.46,47 In one study, prolonging therapy to 10 days reduced mortality to zero; however, prolonging medical therapy beyond 10 days did not improve the remission rate.48 In the past 10 years, the Oxford regimen has been modified by the introduction of ciclosporin and, more recently, infliximab as treatment options. Other biological agents, such as visilizumab, have also been tested, but experience with these agents is still limited. Ciclosporin The use of intravenous ciclosporin in the management of severe ulcerative colitis resulted from a North American placebo-controlled randomized trial published in 1994 that reported the efficacy of 4 mg/kg of intravenous ciclosporin given to patients not responding to intravenous glucocorticosteroids.10 Many open studies confirmed that intravenous ciclosporin, at a dose of 2–4 mg/ kg/day, induces clinical improvement in >50% of the patients in the short term.10–13 Furthermore, a European double-blind controlled trial showed that ciclosporin alone is at least as effective as corticosteroids in the treatment of patients with severe ulcerative colitis.11 The same group also performed a randomized, double-blind study comparing 4 mg/kg with 2 mg/kg intravenous ciclosporin. The study showed that highdose ciclosporin has no additional clinical benefit over low-dose ciclosporin in the treatment of severe attacks of ulcerative colitis. Although differences in adverse events were not observed in the short term, it was concluded that because most ciclosporin-associated adverse events are dose dependent, the use of 2 mg/kg should improve the long-term toxicity profile of the agent.12 Although the value of ciclosporin for the management of severe ulcerative colitis has been accepted in most referral centers, concerns about toxicity have prevented its use in many hospitals. Ciclosporin can lead to severe side effects (e.g. hypertension, renal failure, neurotoxicity and hypertrichosis), which lead to death in a



significant minority of patients, thus limiting its use. The benefits of avoiding colectomy should, therefore, always be balanced against the risk of inducing profound immunosuppression and severe side effects. Furthermore, in many instances, administration of ciclosporin only delays and does not prevent colectomy. A frequency >8 stools per day or CRP >45 mg/l at day 3 has been shown to predict the need for colectomy.25 If remission is achieved by intravenous ciclosporin, oral ciclosporin is continued for 3–6 months. Campbell et al. have now described the longterm outcome of a large series of patients treated with ciclosporin for severe colitis refractory to intravenous steroids.13 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 on discharge from the hospital in association with oral ciclosporin as bridge therapy.13 A recent systematic review of the literature on severe ulcerative colitis has shown that the evidence indicating that ciclosporin is more effective than standard corticosteroid therapy is weak, and that ciclosporin does not avoid the overall need for colectomy.17 On the basis of these observations, the systematic use of ciclosporin in severe ulcerative colitis is still debated. Infliximab Monoclonal anti-tumor necrosis factor antibodies (i.e. infliximab) have now been used to treat severe ulcerative colitis. The first randomized controlled trial of infliximab for ulcerative colitis did not support its use in the management of moderately active glucocorticoid-resistant ulcerative colitis; however patients with severe disease were specifically excluded from the study.14 Since then, data from two randomized controlled clinical trials (ACT1 and ACT2), which included over 700 patients with moderate-tosevere ulcerative colitis, have been published in a single article.15 Infliximab, given intravenously at the dose of 5 mg/kg, at 0, 2 and 6 weeks, was effective at inducing clinical remission, healing the lesions and had a steroid sparing effect. It was not clear, however, how many patients were included in these trials who had severe ulcerative colitis requiring hospital admission and the institution of an intensive treatment regimen. A Scandinavian trial has recently shown that infliximab given as a single 5 mg/kg infusion


is significantly more effective than placebo at avoiding colectomy in patients with severe ulcerative colitis that is refractory to corticosteroids.16 The study, however, refers to a follow-up of 3 months and provides no information on the long-term follow-up. Three small, uncontrolled studies on infliximab in severe ulcerative colitis were presented as abstracts at the 2006 Digestive Disease Week (one has subsequently appeared as a full paper). One study was negative and two were in favor of the use of infliximab.49–51 Infliximab, like ciclosporin, can give rise to serious side effects because of immunogenicity (allergic reactions or autoimmunity) and immunosuppression (e.g. tuberculosis and other infections, and possibly neoplasic changes).2,13–15 Considering that worldwide, more than 575,000 patients have so far been treated with infliximab, its safety profile is considered good (Centocor, data on file). Also, data from the TREAT registry referring to 6,290 patients, of whom 3,179 received infliximab and 3,111 received other therapies, have shown that the rates of mortality and serious infections observed with infliximab were similar to other therapies and lower than with corticosteroids. No increase in incidence of malignancy associated with infliximab versus other therapies was identified.52 In summary, the use of infliximab as a treatment for severe ulcerative colitis seems promising, but is not yet clearly defined. In particular, whether early use of infliximab will prevent colectomy is uncertain. The current management of severe ulcerative colitis, including the role of infliximab, is summarized in Figure 2. Other therapies Visilizumab is a humanized IgG2 monoclonal antibody that binds the CD3 epsilon chain (the invariable chain of the T-cell antigen receptor complex), inducing T-cell apoptosis. Preliminary results of a phase I/II study showed that visilizumab is effective and safe in both the treatment and retreatment of patients with steroid-refractory severe ulcerative colitis. A transient mild-to-moderate cytokine-release syndrome (chills, headache, pyrexia, fatigue and arthralgia), a transient decrease in T-lymphocyte numbers (with a recovery time of about 3 weeks) and transient elevation in Epstein–Barr viral load were routinely observed at each infusion. No opportunistic infections were reported.53



Leukocyte apheresis, a method of therapeutic apheresis that removes patients’ peripheral leukocytes by extracorporeal circulation, seems to be an additional effective and safe option for the management of severe ulcerative colitis, and also in the presence of complications such as toxic megacolon.54 Other measures Nutritional support and intensive intravenous fluid and electrolyte replacement are needed to correct malnutrition, dehydration, and electrolyte and acid–base imbalance. Total parenteral nutrition (TPN) is usually initiated, although controlled trials have not confirmed that TPN or bowel rest are effective.55 Heparin can be given to prevent thromboembolism.2 Controlled trials have demonstrated that there is no benefit to be gained from antibiotics;56 however, they are usually given before surgery to prevent infection. Specific therapy is needed in the presence of Clostridium difficile or cytomegalovirus (CMV). Antidiarrheal agents, opioids and NSAIDs should be avoided, as they can induce toxic megacolon or deterioration of colitis. Complicated severe ulcerative colitis

The major complications of severe ulcerative colitis include toxic megacolon, perforation, massive bleeding and MODS. Toxic megacolon Toxic megacolon is a potentially fatal complication of ulcerative colitis, with an incidence of 10–17% reported in patients admitted to hospital with ulcerative colitis.31,32,57,58 The clinical features of toxic megacolon are usually those of severe colitis. Only in the advanced phase of the disease do abdominal distension, reduced number of bowel sounds, pain and constitutional symptoms appear. The abdomen can be extremely tender. Hypoalbuminemia, electrolyte imbalance and metabolic alkalosis are common findings. The diagnosis of toxic megacolon is classically made on the basis of plain abdominal X-ray film, especially taken in the supine position. Experience on the use of CT in the diagnosis of toxic megacolon is scanty; in one article, CT was reported to detect intra-abdominal complications not revealed on X-ray.59 Patients with toxic megacolon should be placed on bowel rest and TPN, and should receive adequate water and electrolyte repletion to correct


dehydration, electrolyte imbalance and metabolic alkalosis. Daily or twice daily monitoring of clinical, laboratory and radiologic parameters is necessary. Corticosteroids should be given, as in severe colitis. Ciclosporin and infliximab are not usually administered. Approximately half the patients with toxic megacolon will respond to treatment without the need for urgent colectomy. Whether to continue medical therapy or perform elective surgery in these patients remains to be assessed. Urgent colectomy is, however, mandatory for those in whom the colon remains dilatated after 48–72 hours of intravenous corticosteroids (Figure 3). Several techniques have been recommended for colonic decompression (e.g. tubes, rolling, knee–elbow position, hyperbaric oxygen chamber and endoscopic decompression), but there is no evidence of their efficacy.60–63 Severe relapse of ulcerative colitis and toxic megacolon has been documented in the presence of coexisting infections such as C. difficile or CMV; therefore, these infections have to be excluded. CMV infection is associated with a poor response to medical therapy.64,65 In such instances, ganciclovir 5 mg/kg twice daily for 15 days should be commenced immediately.64 Perforation and massive bleeding Perforation and massive bleeding are common in patients with toxic megacolon, and adversely affect the prognosis of severe ulcerative colitis. In years gone by, perforation, massive bleeding and toxic megacolon were referred to collectively as fulminating ulcerative colitis.66 Perforation is a rare complication in patients with ulcerative colitis, occurring in 0.3% of patients.67 As perforation usually occurs in the setting of toxic megacolon, the detection of perforation can be difficult and is revealed only at CT or during surgery. Perforation, revealed by the detection of free gas (gas outside the gut) on X-ray film or CT is an absolute indication for emergency colectomy. The procedure of choice is subtotal colectomy with rectosigmoid mucous fistula. In patients with massive bleeding, transfusion combined with treatment usually stops the bleeding. If, however, the patient requires 6–8 units of blood within 24–48 hours and is still bleeding, emergency colectomy must be considered.68 Proctocolectomy is the procedure of choice.68–70



Multiple organ dysfunction syndrome MODS is a complication of various acute critical diseases including severe ulcerative colitis, in which it has been shown to occur in 6% of patients, with a mortality rate of 72%.20 MODS is mainly caused by the translocation of bacteria and toxins via the impaired intestinal mucosa, followed by the activation of circulating immunocompetent cells with further production of cytokines and other inflammatory mediators responsible for extraintestinal organ dysfunction and/or failure.20 In patients with ulcerative colitis, the recognition of the symptoms of MODS, such as disproportionate tachycardia, polypnea, hypoxemia, oliguria, mental confusion, or jaundice, prompts the instigation of a particularly aggressive therapeutic approach. Patients should be moved to an intensive care unit where oxygen, nutritional support and high doses of antibiotics should be given immediately. Emergency colectomy is mandatory to remove the main site of the bacterial translocation as soon as possible.20 TIMING OF SURGERY

The prognosis of severe ulcerative colitis has been positively affected not only by progress in medical and surgical treatment, but also by the correct timing of surgery, which can be an urgent or emergent treatment (Box 1).

Intravenous steroids (48–72 hours)

Stop oral feeding Total parenteral nutrition Hydrocortisone (100 mg four times daily) (Antibiotics)

Regression

No response

Oral steroids

Surgery

Maintenance

Elective surgery

Figure 3 Clinical algorithm for the management of toxic megacolon adopted at the GI Unit, University of Rome “La Sapienza”. The patient is first admitted for intensive intravenous steroid and antibiotic therapy. If no clear-cut radiologic and clinical response is observed after 24–72 hours of the intensive regimen, urgent colectomy is mandatory. If colon distension subsides, maintenance therapy or elective surgery are the only options available, but which to choose is controversial.

Box 1 Indications for surgery (colectomy). Urgent surgery Severe colitis (after 5–7 days of ineffective treatment) Toxic megacolon (after 48–72 hours of ineffective treatment) Emergent surgery Perforation Massive hemorrhage Multiple organ dysfunction syndrome (MODS)

Urgent surgery

In severe ulcerative colitis, surgery is absolutely mandatory for any patient whose condition worsens or fails to improve significantly over 5–7 days on an intensive medical regimen.69,70 In clinical practice, it is generally accepted that the timing of surgery should be established on the basis of clinical judgment, both from the gastroenterologist and the surgeon. In some clinical trials, however, clinical indices have also been used in the making of surgical decisions.39,42 In the case of toxic megacolon, the indication for colectomy has to be decided earlier, when there has been no significant response after only 48– 72 hours of an intensive intravenous corticosteroid regimen.2,69,70 Colectomy with ileostomy and preservation of the rectum is the generally accepted procedure for urgent surgery. After recovery, all other surgical procedures can be considered. Emergent surgery

Emergent surgery is mandatory for patients with perforation, or massive bleeding or MODS.2,20,67–70


The detection of one or more of these complications indicates the need for hospitalization in an intensive care unit and emergent colectomy; however, in patients with MODS, mortality remains high.20 CONCLUSIONS

Severe ulcerative colitis must be considered a medical emergency even if the mortality rate for patients with this disease is now low. Several factors might have contributed to the reduction in mortality that has been observed over the past 30 years, such as the widespread use of the so-called Oxford regimen, which has now been integrated with the administration of ciclosporin and infliximab, the early detection of complications, the careful timing of surgery and the improved anesthesiological and surgical techniques. As about 30% of severe ulcerative colitis cases continue to need colectomy, however, the



timing of surgery and the collaboration between gastroenterologist and surgeon remain the most important goals in the management of these patients. New therapeutic approaches, in particular biological therapies, are promising, but their role in the management of severe ulcerative colitis remains to be defined.

12

13

14

KEY POINTS ■

An acute attack of severe ulcerative colitis must considered a medical emergency

15

■

The early detection of prognostic factors significantly reduces mortality in patients with severe ulcerative colitis

16

■

The finding of small-bowel distension on X-ray (so-called impending megacolon) identifies patients at high risk of developing toxic megacolon

■

■

■

Ciclosporin or infliximab can be used in patients with severe ulcerative colitis when there is no clear cut clinical response to an intensive treatment regimen with corticosteroids A particularly aggressive therapeutic approach is appropriate in patients with symptoms of multiple organ dysfunction The timing of colectomy remains the most important decision to be made by the gastroenterologist in conjunction with the surgeon

References 1 Sonnenberg A and Koch TR (1989) Period and generation effect on mortality from idiopathic inflammatory bowel disease. Dig Dis Sci 34: 1720–1729 2 Carter MJ et al. (2004) Guidelines for the management of inflammatory bowel disease in adults. Gut 53 (Suppl V): V1–V16 3 Winther KV et al. (2003) Survival and cause-specific mortality in ulcerative colitis: follow-up of a populationbased cohort in Copenhagen County. Gastroenterology 125: 1576–1582 4 Card T et al. (2003) Mortality in Inflammatory Bowel Disease: a population-based cohort study. Gastroenterology 125: 1583–1590 5 Loftus EV Jr (2003) Mortality in inflammatory bowel disease: peril and promise. Gastroenterology 125: 1881–1883 6 Hardy TL and Bulmer E (1933) Ulcerative colitis: survey of 95 cases. Br Med J 2: 812–815 7 Rice-Oxley JM and Truelove SC (1950) Ulcerative colitis: course and prognosis. Lancet 1: 663–666 8 Truelove SC and Witts LJ (1955) Cortisone in ulcerative colitis: final report on a therapeutic trial. Br Med J 2: 1041–1048 9 Truelove SC and Jewell DP (1974) Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet 1: 1067–1070 10 Lichtiger S et al. (1994) Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 330: 1841–1845 11 D’Haens G et al. (2001) Intravenous cyclosporine versus intravenous corticosteroids as single therapy for


17

18

19 20 21 22 23 24 25 26

27

28 29 30

31 32 33

34

35

36

severe attacks of ulcerative colitis. Gastroenterology 120: 1323–1329 Van Assche G et al. (2003) Randomized doubleblind comparison of 4 mg/Kg versus 2 mg/Kg intravenous Cyclosporin in severe ulcerative colitis. Gastroenterology 125: 1025–1031 Campbell S et al. (2005) Cyclosporine use in acute ulcerative colitis: a long term experience. Eur J Gastroenterol Hepatol 17: 79–84 Probert CSJ et al. (2003) Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomized controlled trial. Gut 52: 998–1002 Rutgeerts P et al. (2005) Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 353: 2462–2476 Jarnerot G et al. (2005) Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 128: 1805–1811 Shibolet O et al. (2005) Cyclosporine-A for induction of remission in severe ulcerative colitis. The Cochrane Database of Systematic Reviews Issue 1, Art. No CD004277 Silverberg MS et al. (2005) Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease. Can J Gastroenterol 19 (Suppl A): 5–36 Jalan KN et al. (1969) An experience of ulcerative colitis. Gastroenterology 57: 68–82 Caprilli R et al. (2000) Multiple organ dysfunction in ulcerative colitis. Am J Gastroenterol 95: 1258–1262 Lennard-Jones JE et al. (1975) Assessment of severity in colitis: a preliminary study. Gut 16: 579–584 Caprilli R et al. (1976) Blood pH: a test for assessment of severity on proctocolitis. Gut 17: 763–769 Caprilli R et al. (1978) Salt loosing diarrhoea in idiopathic proctocolitis. Scand J Gastroenterol 13: 331–335 Caprilli R et al. (1980) Risk factors in toxic megacolon. Dig Dis Sci 25: 817–822 Travis SPL et al. (1996) Predicting outcome in severe ulcerative colitis. Gut 38: 905–910 Ahmad T et al. (2006) Genetics of inflammatory bowel disease: the role of HLA complex. World J Gastroenterol 12: 3628–3635 Ho GT et al. (2006) ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis: discrimination of critical variants using a gene-wide haplotype tagging approach. Hum Mol Genet 15: 797–805 Caprilli R et al. (1987) Early recognition of toxic megacolon. J Clin Gastroenterol 9: 160–164 Chew CN (1991) Small bowel gas in severe ulcerative colitis. Gut 32: 1535–1537 Caprilli R and Onori L (1992) Pathogenesis of gastrointestinal distension in severe ulcerative colitis: a hypothesis. Gastroenterol Int 5: 268–272 Jones JH and Chapman M (1969) Definition of megacolon in colitis. Gut 10: 562–564 Latella G et al. (2002) GI distension in severe ulcerative colitis. Am J Gastroenterol 97: 1169–1175 Mourelle M et al. (1995) Induction of nitric oxide synthase in colonic smooth muscle from patients with toxic megacolon. Gastroenterology 109: 1497–1502 Onori L et al. (2005) 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 11: 5677–5684 Carbonnel F et al. (1994) Colonoscopy of acute colitis. A safe and reliable tool for assessment of severity. Dig Dis Sci 39: 1550–1557 Carbonnel F et al. (2000) Predictive factors of outcome of intensive intravenous treatment for attacks of ulcerative colitis. Aliment Pharmacol Ther 14: 273–279



37 Buckell NA et al. (1980) Depth of ulceration in acute colitis. Correlation with outcome and clinical and radiological features. Gastroenterology 79: 19–25 38 Naber AHJ and de Jong DJ (2003) Assessment of disease activity in inflammatory bowel disease; relevance for clinical trials. Neth J Med 61: 105–110 39 Seo M (1992) An index of disease activity in patients with ulcerative colitis. Am J Gastroenterol 87: 971–976 40 Walmsley RS et al. (1998) A simple clinical colitis activity index. Gut 43: 29–32 41 Su C et al. (2002) Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis. Am J Gastroenterol 97: 2577–2584 42 Lindgren SC (1998) Early predictors of glucocorticoid treatment failure in severe and moderately severe attacks of ulcerative colitis. Eur J Gastroenterol Hepatol 10: 831–835 43 Higgins PDR et al. (2005) Is endoscopy necessary for the measurement of disease activity in ulcerative colitis? Am J Gastroenterol 100: 355–361 44 Truelove SC et al. (1978) Further experience in the treatment of severe attacks of ulcerative colitis. Lancet 2: 1086–1088 45 Meyers S and Janowitz HD (1985) Corticosteroid therapy of ulcerative colitis. Gastroenterology 89: 1189–1191 46 Powell-Tuck J et al. (1977) A controlled trial of corticotrophin and hydrocortisone in the treatment of severe proctocolitis. Scand J Gastroenterol 12: 971–975 47 Meyers S et al. (1983) Corticotropin versus hydrocortisone in the intravenous treatment of ulcerative colitis. A prospective, randomized, doubleblind clinical trial. Gastroenterology 85: 351–357 48 Meyers S et al. (1987) Predicting the outcome of corticoid therapy for acute ulcerative colitis. Results of a prospective, randomized, double-blind clinical trial. J Clin Gastroenterol 9: 50–54 49 Lees C et al. (2006) Infliximab is effective as rescue therapy for acute severe ulcerative colitis. The initial Edinburgh experience. Gastroenterology 130 (Suppl 2): A-656 50 Walsh A et al. (2006) Acute severe ulcerative colitis: a study of predictors of outcome and efficacy for Cyclosporin and Infliximab. Gastroenterology 130 (Suppl 2): A-84 51 Regueiro M et al. (2006) Infliximab for hospitalized patients with severe ulcerative colitis. J Clin Gastroenterol 40: 476–481 52 Lichtenstein GR et al. (2006) Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry. Clin Gastroenterol Hepatol 4: 621–630


53 Baumgart DC et al. (2005) The phase I/II visilizumab study. A report of safety and efficacy of treatment and retreatment in ulcerative colitis patients refractory to treatment with i.v. steroids. Gut 54 (Suppl VII): A57 54 Sawada K et al. (2005) Leukocytapheresis for management of fulminant ulcerative colitis with toxic megacolon. Dig Dis Sci 10: 1–7 55 McIntyre DB et al. (1986) Controlled trial of bowel rest in the treatment of severe colitis. Gut 27: 481–485 56 Chapman RW et al. (1986) Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in acute, severe ulcerative colitis. Gut 27: 1210–1212 57 Greenstein AJ et al. (1985) Outcome of toxic dilation in ulcerative colitis and Crohn’s colitis. J Clin Gastroenterol 7: 137–143 58 Gan SI and Beck PL (2003) A new look at toxic megacolon: an update and review of incidence, etiology, pathogenesis, and management. Am J Gastroenterol 98: 2363–2371 59 Imbriaco M et al. (2001) Toxic megacolon. Role of CT in evaluation and detection of complications. Clin Imaging 25: 349–354 60 Present DH et al. (1988) Medical decompression of toxic megacolon by “rolling”. J Clin Gastroenterol 10: 485–490 61 Panos MS et al. (1993) Toxic megacolon: the knee-elbow position relieves bowel distension. Gut 34: 1726–1727 62 Buchman AL (2001) Hyperbaric oxygen therapy for severe ulcerative colitis. J Clin Gastroenterol 33: 337–339 63 Riedel L (1989) Endoscopic decompression in toxic megacolon. Surg Endosc 3: 51 64 Cottone M et al. (2001) Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn’s colitis. Am J Gastroenterol 96: 773–775 65 Kambham N et al. (2004) Cytomegalovirus infection in steroid-refractory ulcerative colitis: a case-control study. Am J Surg Pathol 28: 365–373 66 Zer M et al. (1972) Pitfalls in the surgical management of fulminating ulcerative colitis. Dis Colon Rectum 15: 280–287 67 Softley A et al. (1988) Perforation of the intestine in IBD. An OMGE survey. Scand J Gastroenterol 23 (Suppl 144): 24–26 68 Robert JH et al. (1990) Management of severe hemorrhage in ulcerative colitis. Am J Surg 159: 550–555 69 Jewell DP et al. (1991) Working Team Report. Indications and timing of surgery for severe ulcerative colitis. Gastroenterol Int 4: 161–164 70 Cohen JL (2005) Practice parameters for the surgical treatment of ulcerative colitis. Dis Colon Rectum 48: 1997–2009

Competing interests The authors declared they have no competing interests.
