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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Patients
  7. Prior therapy
  8. Intravenous ciclosporin and concurrent therapy
  9. Subsequent therapy
  10. Outcome of therapy
  11. Adverse effects
  12. Discussion
  13. References

Background : Intravenous ciclosporin for acute, severe colitis is usually administered in a dose of 4 mg/kg/day, with concurrent intravenous steroids. This is associated with considerable morbidity. We have been using a low-dose regimen, most commonly without concurrent steroids, for seven years, and present the outcome.

Methods : Records of all patients admitted for severe ulcerative colitis, treated by one physician over seven years, were reviewed.

Results : Thirty-one patients received low-dose intravenous ciclosporin (2 mg/kg/day) for a median 8 days. Eleven early patients received concurrent intravenous corticosteroids. Three patients had hypertension requiring dose reduction, one elevated creatinine and one elevated liver enzymes (all transient), and four experienced infection (two arm cellulitis, one perianal abscess, one post-operative wound infection). Twenty-four patients (77%) avoided urgent colectomy, and were discharged on oral ciclosporin and azathioprine. After a median 18 months (range 3–77), 14 patients (45% of total) avoided colectomy, of whom eight had flares responding to medical therapy and two had persistent, mildly active disease.

Conclusions : Low-dose intravenous ciclosporin (2 mg/kg/day), usually used as a monotherapy and followed by azathioprine, achieves similar long-term efficacy to higher dose ciclosporin combined with steroids in severe acute ulcerative colitis. Morbidity appears to be low.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Patients
  7. Prior therapy
  8. Intravenous ciclosporin and concurrent therapy
  9. Subsequent therapy
  10. Outcome of therapy
  11. Adverse effects
  12. Discussion
  13. References

Approximately 15% of patients with ulcerative colitis experience fulminant episodes requiring admission to hospital during the course of their illness.1 Forty percent of such patients will fail to achieve remission with intravenous corticosteroids.2 In the past decade, intravenous ciclosporin at a dose of 4 mg/kg/day, with concurrent intravenous steroids, has become an established therapy in severe steroid-resistant ulcerative colitis, sparing 60–90% of patients from urgent colectomy.3–11 Some responders to ciclosporin will ultimately relapse, but 30–50% will not require surgery during long-term follow-up,5, 7–9, 11 particularly if also established on azathioprine.6, 10

Use of ciclosporin is, however, associated with considerable morbidity. Serious complications such as Pneumcystis carinii pneumonia and seizures may occur in as many as 12% of patients in large series, and deaths have been reported.5, 10, 12 Less serious but nevertheless troubling side effects, including hypertension, liver and renal impairment, tremor, paraesthesiae and headache, occur in up to 50% of patients.3, 9, 10, 12

One strategy to lessen the adverse effects of therapy is to use ciclosporin as monotherapy, avoiding the morbidity associated with concurrent corticosteroids.13 A second approach to decreasing side effects is to reduce the dose of ciclosporin. Actis et al., using low-dose intravenous ciclosporin (2 mg/kg/day) in the acute phase of treatment, have reported short term outcomes that are comparable with those of high-dose therapy, and possibly with less toxicity.14, 15 One randomized trial showed a similar acute response rate in 35 patients treated with low-dose intravenous ciclosporin when compared to 35 treated with a higher dose, although the difference between actual mean doses was modest (1.82 compared with 2.65 mg/kg/day).16 In another case series, an intermediate dose of ciclosporin (2.5 mg/kg/day) achieved similar response rates to those reported with higher doses.17

We have been using a low-dose regimen of intravenous ciclosporin (2 mg/kg/day) routinely in patients admitted with acute, severe ulcerative colitis since 1996, in recent years without concurrent intravenous high-dose corticosteroids. Patients who have initially responded have been treated with azathioprine and commenced on oral ciclosporin prior to hospital discharge. In this study we report both short and long-term outcomes in these patients.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Patients
  7. Prior therapy
  8. Intravenous ciclosporin and concurrent therapy
  9. Subsequent therapy
  10. Outcome of therapy
  11. Adverse effects
  12. Discussion
  13. References

We examined the medical records of all patients admitted to our institution who received intravenous ciclosporin at a dose of 2 mg/kg/day for ulcerative colitis, under the care of a single physician (M.A.K.). Ciclosporin was used in severe colitis, usually with patients experiencing a bowel frequency of 10 or more per day with bleeding, and severe inflammation on sigmoidoscopy. Most patients had also been unresponsive to at least a week's treatment with corticosteroids.

All patients had been diagnosed with ulcerative colitis on the basis of previous colonoscopy with biopsies. The most recent colonoscopy report was used to estimate the extent of disease; left sided colitis was defined as inflammation not extending beyond the splenic flexure. An ulcerative colitis disease activity index (UCDAI), with a maximum score of 12,18 was estimated from the admitting clinician's assessment. A variation of the Truelove–Witts criteria, with a maximum score of 21, was also estimated from the medical records.3, 4 The presence of megacolon was determined from the radiologist's report of colonic dilatation of 6 cm or greater on a plain abdominal film.19

Ciclosporin was infused by continuous intravenous infusion beginning at 2 mg/kg/day, and blood levels were routinely measured on day 3 of infusion by monoclonal assay. The dose was only adjusted for toxicity, or for blood levels < 100 or > 300 ng/mL. Vital signs were recorded four times daily, and electrolytes, creatinine and liver function tests were measured serially during therapy. Hypertension was defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg, sustained for two consecutive days during therapy, while an increase in creatinine > 30% or liver enzymes > 50% above baseline values were taken to indicate nephrotoxicity and hepatotoxicity, respectively.4 Oral 5-acetyl salicylic acid (5-ASA) compounds were continued if tolerated, and azathioprine therapy was continued if previously commenced, or initiated during the hospital admission in the absence of contraindications. Low-dose heparin was routinely administered subcutaneously over the duration of the admission as prophylaxis against deep venous thrombosis.

Patients were closely observed by both a gastroenterologist and a surgeon. Intravenous ciclosporin was ceased when clear clinical improvement was evident, and oral ciclosporin was then commenced. Pneumcystis carinii pneumonia prophylaxis was not given, on the grounds that the risk of infection was less if concurrent steroids were minimized. Urgent surgery was defined as the need for colectomy during the same hospital admission, while delayed surgery took place on a subsequent admission to hospital.

Data are presented as medians and ranges, or as means ± standard deviation when normally distributed.

Patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Patients
  7. Prior therapy
  8. Intravenous ciclosporin and concurrent therapy
  9. Subsequent therapy
  10. Outcome of therapy
  11. Adverse effects
  12. Discussion
  13. References

Thirty-one patients (16 male, median age 38, range 16–65 years) were treated for severe ulcerative colitis with low-dose intravenous ciclosporin (2 mg/kg/day), between 1996 and 2002 (Table 1). The median time since initial diagnosis was 21 months (range 0–324); two patients had newly presented and six had been diagnosed within the previous 6 months. The median duration of the current flare-up was 4 weeks (range 1.5–360 weeks). The median UCDAI was 10 (range 7–12), while the median modified Truelove–Witts score was 14 (range 8–19). Four patients presented with toxic megacolon, while seven patients (23%) had left-sided colitis.

Table 1.  Characteristics of 31 consecutive patients treated with low-dose intravenous ciclosporin for severe ulcerative colitis. Timing of surgery and follow-up is taken from the first day of intravenous ciclosporin therapy
Patient numberSexAgeDisease duration (months)UCDAIModified Truelove & Witts scoreLeft sided diseaseDuration IV ciclosporin (days)Concurrent high-dose IV steroidUrgent surgery (days)Delayed surgery (months)Follow-up without surgery (months)
  1. UCDAI, Ulcerative colitis disease activity index (see reference 18); modified Truelove and Witts score, see references 3 and 4.

 1M33481017 6x  77
 2F2835912 5x 9 
 3M38651119 10   76
 4F52911116 6x 10 
 5F6019915x8x  71
 6F601511014 11x 3.5 
 7M52981113x8x  62
 8M6510878 9   54
 9M5310912 7 9  
10F58324911 10x 2 
11F34151011x7   50
12M306710x5  2 
13M2081115 8x14  
14F31131212 4x 3.5 
15M3721914x7  7 
16M231131115 9x12  
17F1643913 7  2 
18M38201015x9  6 
19M1761214 7 10  
20F38721018 12 7  
21M42241016 13  9 
22F3210916 11   20
23M4052911x7   8
24M1631013 4   15
25F462041216 10   12
26F310.51213 7 7  
27M460912 8   7
28F5331114 10   11
29F27171112 5   6.5
30M2541216 8x  2.5
31F531561217 3 3  
Median 38211014 8   17.5

Prior therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Patients
  7. Prior therapy
  8. Intravenous ciclosporin and concurrent therapy
  9. Subsequent therapy
  10. Outcome of therapy
  11. Adverse effects
  12. Discussion
  13. References

Seventeen patients (55%) received intravenous corticosteroids prior to ciclosporin, either in another institution or in our hospital, while another eight had received a course of oral corticosteroids immediately prior to admission. Patients who had received prior steroids had not responded and hence, were treated with ciclosporin. Six patients (19%) had not received corticosteroids in the recent past, and ciclosporin was used as the first line therapy for a severe episode. Four of these patients had severe, persistent disease that had responded poorly to steroids in the past, and two had contraindications to corticosteroids (previous reported anaphylactic reaction to intravenous steroids; labile psychological state).

Twenty-four patients (77%) were taking oral 5-ASA compounds before admission. Ten patients (32%) were already established on azathioprine, although the dose had been suboptimal (< 2 mg/kg/day) in two of these.

Intravenous ciclosporin and concurrent therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Patients
  7. Prior therapy
  8. Intravenous ciclosporin and concurrent therapy
  9. Subsequent therapy
  10. Outcome of therapy
  11. Adverse effects
  12. Discussion
  13. References

The mean dose of intravenous ciclosporin was 2.04 (± 0.14) mg/kg/day (range 1.82–2.47), which resulted in mean blood levels of 225 (± 69) ng/mL (range 122–407) on day 3 of treatment. Dose adjustment was required in three patients only. Intravenous ciclosporin was given for a median of 8 days (range 3–13).

Eleven patients (35%) received high-dose intravenous corticosteroids concurrently, predominantly in the first four years of the series (1996–99). After this time our practice changed to avoid concurrent corticosteroid use. Another 11 patients received intravenous or oral steroids that were tapered to zero rapidly after admission, usually over 3–5 days. This related to these patients having been on corticosteroids prior to admission, with the need to wean gradually. Nine patients (29%) received no concurrent corticosteroid.

Subsequent therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Patients
  7. Prior therapy
  8. Intravenous ciclosporin and concurrent therapy
  9. Subsequent therapy
  10. Outcome of therapy
  11. Adverse effects
  12. Discussion
  13. References

Twenty-two of the 24 patients who avoided urgent colectomy were discharged on oral ciclosporin, which was given for a median of 75 days (range 15–180 days). Patients were commenced on 5 mg/kg/day by mouth, and the dose was adjusted to achieve a blood level of 100–200 ng/mL. Twenty-one patients were discharged on oral azathioprine and one on 6-mercaptopurine. In the early part of the series, when corticosteroids had been administered concurrently with ciclosporin, they were tapered rapidly in the month after discharge from hospital.

Outcome of therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Patients
  7. Prior therapy
  8. Intravenous ciclosporin and concurrent therapy
  9. Subsequent therapy
  10. Outcome of therapy
  11. Adverse effects
  12. Discussion
  13. References

Seven patients (23%) required urgent colectomy a mean of 8.9 (± 3.6) days (range 3–14) after beginning intravenous ciclosporin. A further 10 patients (32%) required delayed surgery, a median of 2.8 months (range 2–9) after beginning ciclosporin. The remaining 14 patients (45%) did not require surgery over a median of 17.5 months (range 2.5–77) follow-up. Of this latter group, eight patients had experienced one or more flares which responded to corticosteroids and, in one case, to re-treatment with intravenous ciclosporin, 3 years after the index admission. Two others had persisting symptoms of mildly active disease, while four had remained in remission without further flares of disease activity. When restricting the analysis to the 24 patients with extensive disease beyond the splenic flexure, 71% of patients were spared urgent colectomy and 42% avoided surgery on follow-up.

Seven patients had left sided colitis. None required urgent surgery, but three underwent delayed colectomy between 2 and 7 months after admission. Four have not required surgery during follow-up of between 8 and 71 months; three have experienced one or more recurrent flares responsive to medical therapy, while one has had persistent mildly active disease.

Of the 20 patients who received intravenous ciclosporin without high-dose concurrent corticosteroid (median UCDAI 10, range 7–12), five required urgent colectomy and five required delayed surgery. This was comparable with the 11 patients who received concurrent high-dose intravenous steroids (median UCDAI 11, range 9–12), of whom two required urgent colectomy and five required delayed surgery.

Four patients had colonic dilatation of 6 cm or greater on plain abdominal radiographs. Three required urgent colectomy (none with perforation), while in the other, dilatation resolved over 8 days of intravenous therapy, and surgery has not been required during 2.5 months follow-up.

Adverse effects

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Patients
  7. Prior therapy
  8. Intravenous ciclosporin and concurrent therapy
  9. Subsequent therapy
  10. Outcome of therapy
  11. Adverse effects
  12. Discussion
  13. References

Low-dose intravenous ciclosporin was well tolerated by most patients and there were no deaths, major infective episodes or seizures. Ciclosporin was ceased prematurely in three patients, one after 7 days due to a doubling of creatinine over baseline values (this patient required urgent colectomy on day 10), one after 4 days due to the identification of Clostridium difficile in a stool sample taken on day 1 (this patient ultimately had a good outcome) and one after 4 days due to profound thrombocytopenia (this patient required delayed colectomy at 3.5 months), though the thrombocytopenia was thought most likely induced by heparin.

Five patients had a sustained systolic blood pressure over 140 mmHg, three of whom also had a sustained diastolic blood pressure over 90 mmHg, although in four of these patients the blood pressure was already elevated prior to therapy. Three patients had their ciclosporin dose reduced due to hypertension. In one other patient, hypertension and tremulousness were attributable to a dosing error during one 24 h period and resolved on resuming the correct dose of ciclosporin.

One patient experienced asymptomatic, transient elevation of alanine aminotransferase to three times the upper limit of normal, which normalized despite continuing ciclosporin in oral form.

There were two cases of minor infection at intravenous cannula sites, one of subsequent perianal abscess and one of minor abdominal wound infection following urgent colectomy. In patients undergoing surgery, the other complications were post-operative bleeding in two patients necessitating repeat laparotomy, and small bowel volvulus around the ileostomy in one patient.

During the oral phase of ciclosporin therapy, one patient complained of paraesthesiae and one of worsening frequency of migraine.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Patients
  7. Prior therapy
  8. Intravenous ciclosporin and concurrent therapy
  9. Subsequent therapy
  10. Outcome of therapy
  11. Adverse effects
  12. Discussion
  13. References

In our experience of 31 patients with severe ulcerative colitis over 8 years, low-dose intravenous ciclosporin (2 mg/kg/day) appeared to be approximately as effective as the published use of high-dose therapy (4 mg/kg/day) in avoiding the need for urgent colectomy, even when used as monotherapy. Furthermore, low-dose ciclosporin was associated with a low incidence of side effects when compared with reports of higher dose regimens. The disease activity in our patients was similar to that reported in previous trials of intravenous ciclosporin,3, 4, 13 where patients with modified Truelove–Witts scores of 10 or more were enrolled. One of our patients had an estimated score less than 10 at admission but was treated with ciclosporin because of the failure of other medical therapy. The patients in our series represent a subset of those admitted for colitis. Corticosteroids generally remain first line therapy. The patients in this reported series are all the patients who failed this treatment and were treated with ciclosporin.

Intravenous ciclosporin, at the established dose of 4 mg/kg/day, has had a major impact on the treatment of patients with severe ulcerative colitis in recent years, sparing between 60 and 90% of patients the need for urgent surgery where colectomy would previously have been the only remaining option.3–11 Our acute response rate of 77% with a low-dose regimen is well within this range, and it supports the approach of Actis et al. who reported a short term response of 69% in their series of 40 patients treated over a decade,15 and the preliminary report of Van Assche et al. of 83% in 35 patients.16 Even excluding the 25% of our patients with left sided colitis, who might have represented a less acutely unwell group, our acute response rate was 71%.

Ciclosporin is a potentially toxic drug, and both major and minor adverse reactions are not uncommon with high-dose regimens, even when blood levels are closely monitored.3, 5, 9, 10 Concurrent use of corticosteroids can add to morbidity by adding steroid-related side effects, or by potentiating the risk of infection. Recent data indicate that monotherapy with high-dose intravenous ciclosporin may be as effective as high-dose intravenous corticosteroids.13 The favourable acute response (75%) in our 20 patients treated with low-dose intravenous ciclosporin without concurrent high-dose steroids suggests that monotherapy is also appropriate with a low-dose ciclosporin regimen, with the limitation that our data are uncontrolled.

The side effect profile that we report appears favourable when compared with high-dose regimens. In particular, there were no deaths and no incidence of P. carinii pneumonia; the latter may partly be attributable to minimizing the use of corticosteroids. Adverse reactions to ciclosporin itself could only be implicated in one of the three patients in whom therapy had to be withdrawn prematurely, in that case due to renal impairment. Only two patients (6%) required dose reduction for hypertension, and acute neurological events were scarce. Infective complications, a particular concern with the use of potent immunosuppressants, were relatively minor and occurred in four patients only (13%).

As well as demonstrating short term efficacy, our low-dose intravenous ciclosporin regimen achieved a similar long-term outcome to that reported for higher doses. Of our 31 patients, 14 (45%) avoided the need for colectomy on prolonged follow-up compared with a range of 30–50% after initial treatment with 4 mg/kg/day intravenous ciclosporin.5, 7–9, 11 Our practice of routinely treating patients with azathioprine after discharge, in addition to oral ciclosporin, may well have contributed to our figure being at the higher end of the historical range.6, 10 It has recently been suggested that azathioprine without oral ciclosporin may be sufficient to maintain remission achieved with intravenous ciclosporin,20 though this may not be appropriate given the known period of several months which is often required for azathioprine to exert an effect.21

In summary, our group of 31 patients treated with low-dose intravenous ciclosporin for severe ulcerative colitis, and followed over a prolonged period, had short and long-term efficacy similar to that reported for high-dose ciclosporin, and with a favourable side effect profile. Our data, together with that of at least two other groups,14–16 support a change from the established high-dose regimen (4 mg/kg/day) to a low-dose (2 mg/kg/day) of intravenous ciclosporin, together with minimization of concurrent corticosteroids. The publication of prospective, randomized controlled data together with long-term follow-up is awaited.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Patients
  7. Prior therapy
  8. Intravenous ciclosporin and concurrent therapy
  9. Subsequent therapy
  10. Outcome of therapy
  11. Adverse effects
  12. Discussion
  13. References
  • 1
    Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis. Part 1: short-term prognosis. Gut 1963; 0: 3008.
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    Truelove SC, Willoughby CP, Lee EG, Kettlewell MG. Further experience in the treatment of severe attacks of ulcerative colitis. Lancet 1978; 2: 10868.
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    Lichtiger S, Present DH. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis. Lancet 1990; 336: 169.
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    Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994; 330: 18415.
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    Santos J, Baudet S, Casellas F, Guarner L, Vilaseca J, Malagelada JR. Efficacy of intravenous cyclosporine for steroid refractory attacks of ulcerative colitis. J Clin Gastroenterol 1995; 20: 2859.
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    Fernandez-Banares F, Bertran X, Esteve-Comas M, et al. Azathioprine is useful in maintaining long-term remission induced by intravenous cyclosporine in steroid-refractory severe ulcerative colitis. Am J Gastroenterol 1996; 91: 24989.
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    Hyde GM, Thillainayagam AV, Jewell DP. Intravenous cyclosporin as rescue therapy in severe ulcerative colitis: time for a reappraisal? Eur J Gastroenterol Hepatol 1998; 10: 4113.
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    Stack WA, Long RG, Hawkey CJ. Short- and long-term outcome of patients treated with cyclosporin for severe acute ulcerative colitis. Aliment Pharmacol Ther 1998; 12: 9738.
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    Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol 1999; 94: 158792.
    Direct Link:
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    McCormack G, McCormick PA, Hyland JM, O'Donoghue DP. Cyclosporin therapy in severe ulcerative colitis: is it worth the effort? Dis Colon Rectum 2002; 45: 12005.
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    Cohen RD. Intravenous cyclosporine in severe ulcerative colitis: ready to stand alone? Gastroenterology 2001; 120: 15413.
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    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: 13239.
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    Actis GC, Ottobrelli A, Pera A, et al. Continuously infused cyclosporine at low-dose is sufficient to avoid emergency colectomy in acute attacks of ulcerative colitis without the need for high-dose steroids. J Clin Gastroenterol 1993; 17: 103.
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    Actis GC, Aimo G, Priolo G, Moscato D, Rizzetto M, Pagni R. Efficacy and efficiency of oral microemulsion cyclosporin versus intravenous and soft gelatin capsule cyclosporin in the treatment of severe steroid-refractory ulcerative colitis: an open-label retrospective trial. Inflamm Bowel Dis 1998; 4: 2769.
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    Van Assche G, D'Haens G, Noman M, et al. Randomized double blind comparison of 4 mg/kg versus 2 mg/kg IV cyclosporine in severe ulcerative colitis. Gastroenterology 2002; 122: A668 (Abstract).
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    Rowe FA, Walker JH, Karp LC, Vasiliauskas EA, Plevy SE, Targan SR. Factors predictive of response to cyclosporin treatment for severe, steroid-resistant ulcerative colitis. Am J Gastroenterol 2000; 95: 20008.
    Direct Link:
  • 18
    Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987; 317: 16259.
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    Jones JH, Chapman M. Definition of megacolon in colitis. Gut 1969; 10: 5624.
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    Domenech E, Garcia-Planella E, Bernal I, et al. Azathioprine without oral ciclosporin in the long-term maintenance of remission induced by intravenous ciclosporin in severe, steroid-refractory ulcerative colitis. Aliment Pharmacol Ther 2002; 16: 20615.
  • 21
    Sandborn WJ, Tremaine WJ, Wolf DC, et al. Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group. Gastroenterol 1999; 117: 52735.