Review in depth 239

Ciclosporin and refractory colitis

A. Barney Hawthorne

Intravenous ciclosporin 4 mg/kg daily is rapidly effective shows good response rates, but further studies are
as a salvage therapy for patients with refractory colitis, needed to confirm optimal use of this potent, but
who would otherwise face colectomy, but its use is hazardous, therapy. Eur J Gastroenterol Hepatol 15:239–
controversial because of risk of toxicity, and long-term 244 & 2003 Lippincott Williams & Wilkins
failure rate. Opportunistic infections remain a serious
concern, with a number of reports of death related to
Downloaded from http://journals.lww.com/eurojgh by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 08/09/2021

ciclosporin. Renal and neurotoxicity are also well- European Journal of Gastroenterology & Hepatology 2003, 15:239–244

recognized. The drug should not be continued for more Keywords: ulcerative colitis, ciclosporin, immunosuppressive agents
than 3–6 months and its main role is as a bridge to
Department of Medicine, University Hospital of Wales, Cardiff, UK.
azathioprine or 6-mercaptopurine. Risks of toxicity can be
reduced by using lower doses (2 mg/kg/day Correspondence to Dr A. Barney Hawthorne, Department of Medicine, University
Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK.
intravenously), by oral microemulsion ciclosporin, or by Tel: +44 (0)29 2074 2183; fax: +44 (0)29 2074 5131;
monotherapy without corticosteroids. Preliminary evidence e-mail: Barney.Hawthorne@UHW-TR.wales.nhs.uk

Introduction prevents translocation of a family of transcription

Treatment with intravenous corticosteroids remains the factors, nuclear factor activated T cells (NF-AT) [5],
mainstay of treatment in hospital for severe ulcerative which reduces activation of genes for interleukin (IL)-
colitis, but the colectomy rate for treatment failure is 2, IL-3, IL-4, granulocyte macrophage colony-stimulat-
about 30% [1]. These figures have not changed sub- ing factor, tumour necrosis factor alpha and interferon
stantially over the past 40 years. Most patients are gamma [6]. T-cell transcription factors AP-1 and NF-
desperate to avoid surgery, because of the need for an kB are also inhibited [7]. Ciclosporin acts predomi-
ileostomy. Although an ileo-anal pouch procedure can nantly on CD4 cells, and in rheumatoid arthritis there
remove the need for long-term ileostomy, it rarely is a shift from Th1 to Th2 type cytokine expression [8].
restores bowel function to normality. Patients are
usually keen to pursue intensive medical therapy to Clinical evidence of benefit
avoid surgery. The use of ciclosporin as a rescue The first report of ciclosporin use in ulcerative colitis
therapy in severe colitis is the only significant advance was published in 1984 [9]. The use of ciclosporin
in medical therapy since the introduction of intra- became more widespread after publication of a small
venous corticosteroids, yet the role of this drug remains placebo controlled trial from Chicago and New York by
controversial, with doubts about side effects and long- Lichtiger and colleagues [10]. This study randomized
term outcomes. A survey reported in 1997 showed that 20 hospital inpatients with severe colitis unresponsive
only 26% of Canadian gastroenterologists used ciclo- to 7 days of intravenous corticosteroids, to receive
sporin [2]. More recent surveys have shown the drug is ciclosporin 4 mg/kg daily by continuous intravenous
used by just under half of gastroenterologists in the UK infusion, or placebo. Nine of 11 patients receiving
[3], USA and Europe [4], and only in very small active drug had improvement within days, while none
numbers of patients. of the placebo group improved. Although the trial was
very small, and did not include sigmoidoscopic assess-
Mode of action ment, it established that ciclosporin worked quickly,
In 1970, a researcher at Sandoz Inc. collected soil and could produce high response rates in the short
samples during his summer holiday. After his return to term, for patients who would otherwise undergo colect-
work, the microbiology department isolated a new omy. The trial established the intravenous infusion of
strain of fungus (Tolypocladium inflatum Gams) and, 4 mg/kg/day as the standard dose, and the same authors
from this, a peptide was isolated with potent immuno- published practical guidelines on ciclosporin usage [11].
suppressive, but no myelotoxic activity. Ciclosporin is a
lipophilic cyclic undecapeptide that binds with high Although no other placebo controlled studies have been
affinity to its cytoplasmic receptor protein cyclophilin. published, there have been many uncontrolled reports
The ciclosporin–cyclophilin complex specifically and of ciclosporin use in refractory colitis, and these are
competitively binds to and inhibits calcineurin, a cal- summarized in Table 1. These studies provide support
cium and calmodulin dependent phosphatase. This for the high short-term response rates, with a mean
0954-691X & 2003 Lippincott Williams & Wilkins DOI: 10.1097/01.meg.0000049996.68425.4f

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
240 European Journal of Gastroenterology & Hepatology 2003, Vol 15 No 3

Table 1 Case series of ten or more patients treated with ciclosporin for refractory ulcerative colitis
Initial
Number of Initial dose response
First author, year and reference patients (mg/kg) Ciclosporin level (ng/ml) (%) Long-term response

Lichtiger, 1990 [45] 15 i.v., 4 Target, 400–600 (during i.v.) 73 60% response, (40% off steroids) at 6 months
Santos, 1995 [19] 21 i.v., 5 – 76 –
Fernandez-Banares, 1996 [13] 13 i.v., 4 – 93 69% at mean 15 months
Van Gossum, 1997 [46] 29 i.v., 4 – 69 45% at median 12 months
Wenzl, 1998 [47] 14 i.v., 4 Target, 100–400 79 50% at median 4 years
Stack, 1998 [20] 22 i.v., 4 Target, 100–200 82 55% at mean 15 months
Hyde, 1998 [48] 50 i.v., 4 Target, 100–200 (trough) 56 40% avoid colectomy at mean 19 months
Cohen, 1999 [17] 42 i.v., 4 Mean 360 (during i.v., by HPLC) 86 67% at 1 year, 58% at 5.5 years (66% with purine
analogues, 40% without)
Hermida-Rodriguez, 1999 [49] 15 i.v., 4 – 67 No data after 4 months
Haslam, 2000 [16] 27 i.v., 4 Median 170 62 30% had response maintained
Pooled response 73
Oral and low-dose i.v. studies
Treem, 1995 [50] 14 (paediatric) oral, 4.6–9.6 Target, 150–300 78 28% at 1 year
Carbonnel, 1996 [21] 32 i.v., 1.3–4.6 Mean 279 (during i.v.) 63 28% at 6 months
Actis, 1998 [22] 40 i.v., 2 Target, 60–240 (trough) 65 60%
15 oral, 5 100
Rowe, 2000 [18] 36 i.v., 2.5 200–300 (during i.v.) 69 33% at 9 months
Navazo, 2001 [51] 10 oral, 7–7.5 250–350 (trough) 82 55% at mean 15 months

Pooled results given for high-dose i.v. series, but not for oral or low-dose i.v. series because of heterogeneity. Ciclosporin concentrations are measured by
radioimmunoassay except where indicated. HPLC, high-performance liquid chromatography.

initial response rate (generally meaning avoidance of Nephrotoxicity

colectomy and discharge from hospital on oral medica- Mild, reversible renal impairment in colitis patients
tion) of 73%. These reports showed, however, that the treated with ciclosporin is common. There are only
medium-and long-term response rates were much low- isolated reports of serious renal failure (such as acute
er. Just less than half the patients (47%) avoided renal failure [16], which in this case was reversible),
colectomy in those studies reporting follow-up for more probably because of the short duration of therapy.
than a year. This is still an appreciable proportion, but Acute nephrotoxicity is due to a dose dependent
ciclosporin is clearly not a cure for colitis. Long-term vasoconstriction of afferent and efferent glomerular
remission is more likely if patients are treated with arterioles, resulting in reduced renal blood flow and a
azathioprine or 6-mercaptopurine [12,13]. Combination fall in glomerular filtration rate [23]. The effect can be
therapy does not seem to increase the risk of toxicity reduced by treatment with calcium channel blockers
[14,15], although caution is necessary (see below). It [24], but may be increased by the concomitant prescrip-
seems logical to use oral microemulsion ciclosporin for tion of other nephrotoxic drugs. A rare effect of
3–6 months as a bridge to purine analogue therapy. ciclosporin is a vascular lesion akin to that in haemoly-
tic–uraemic syndrome. This is idiosyncratic and leads
Many questions remain about the use of ciclosporin in to irreversible renal failure. Chronic nephrotoxicity [25]
refractory colitis. These include the risk of major side results from obliterative arteriolopathy, ischaemic col-
effects and whether the long-term success rate in lapse or scarring of glomeruli, vacuolization of tubules,
avoidance of colectomy or achieving remission off and focal tubular atrophy and interstitial fibrosis. A
corticosteroids can justify the considerable risks. The fourth renal problem is tubular dysfunction, resulting in
optimal dose, route of delivery and duration of therapy hyperuricaemia, metabolic acidosis, hypophosphataemia
remain to be clarified. These questions have to be and hypomagnesaemia.
considered in the context of the possibility that safer
drugs will supersede ciclosporin. Infections
The profound immunosuppressive effects of ciclosporin
result in a significant risk of infections. The risk is dose
Toxicity dependent and compounded by co-treatment with
In published case series, the risk of minor side effects corticosteroids, and the general condition of the patient.
ranges from 31% to 51% [16–18], including tremor, Infective complications reported include opportunistic
paraesthesiae, malaise, headache, abnormal liver func- pathogens, particularly Pneumocystis carinii [17–19,26],
tion, gingival hyperplasia and hirsutism. Major compli- but also Nocardia sp. lung abscess [27], Aspergillus
cations are reported with a frequency from 0% to 17% fumigatus pneumonia [28], Listeria monocytogenes menin-
[17–22], including renal, infectious and neurotoxic gitis [16], cytomegalovirus, herpes simplex anal ulcers
effects. and Candida infections [18,29]. Septicaemia from con-

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Review in depth Ciclosporin and refractory colitis Hawthorne 241

ventional infections also occurs, such as Staphylococcus generally aim for whole-blood trough levels of 100–
aureus and Haemophilus influenzae [21]. Deaths are 200 ng/ml using a monoclonal radioimmunoassay.
reported in a number of series or case reports, and
are usually due to overwhelming infection [19,22,26]. Oral treatment
Pneumocystis prophylaxis with co-trimoxazole should be The microemulsion based formulation of ciclosporin
considered if patients are also on high-dose cortico- was developed to overcome problems of poor and
steroids, noting that this can also cause a modest rise in unpredictable absorption of the standard oral prepara-
creatinine. It cannot, however, be stipulated because tion. Oral microemulsion ciclosporin is now used widely
unlike transplant patients, the pre-morbid health of the to initiate immunosuppression after organ transplanta-
individual has usually been good, the duration of tion [35]. An oral dose of 5 mg/kg/day would be equiva-
therapy is short and most opportunistic infections will lent to 2 mg/kg/day intravenously [36]. There are
not be covered by co-trimoxazole. Additional caution is reports of use of oral ciclosporin [37], and Actis and
necessary, because interaction between co-trimoxazole colleagues have published case series [22,36] reporting
and azathioprine to cause bone marrow suppression is good responses to both intravenous doses of 2 mg/kg
predictable. and oral 5 mg/kg daily, without serious side effects.
Table 1 shows that there is a wide range of initial
Neurotoxicity response rates to 4 mg/kg, or more, given daily by the
Minor neurotoxic effects of ciclosporin include tremor, intravenous route, with a mean response rate of 73%. A
burning paraesthesiae, headaches, blurred vision and lower intravenous dose, or oral dose regimens compare
malaise. More serious effects include seizures, coma, favourably with this. Clearly these trials (Table 1) are
spasticity, ataxia, and many other effects [30]. Mechan- widely different, and may have used very different
isms are uncertain, but ciclosporin in rats reduces criteria in patient selection for ciclosporin, but raise the
seizure threshold. The drug is highly lipophilic, binds hope that lower doses may be equally effective. This is
to serum lipids, and readily penetrates the blood–brain borne out by a recent randomized controlled trial in 70
barrier. Magnetic resonance scanning suggests axonal patients, published in abstract form [38] from Leuven,
swelling, and reversible ischaemia may result from Belgium, showing that patients receiving 2 mg/kg intra-
vasoconstriction. These effects are dose related, and venously had an 85% response rate at 3 months, which
reversible, but they can occur at low doses [30] and the was similar to the response rate of 82% on 4 mg/kg.
risk of neurotoxicity may be increased by many factors,
including high-dose corticosteroids [31], hypertension, Monotherapy
and hypomagnesaemia [32]. In transplant patients, low Other strategies to reduce the toxicity of ciclosporin
serum cholesterol predisposes to seizures and neuro- include its use as monotherapy without corticosteroids.
toxicity. In one study, toxicity only occurred in liver The Leuven group have performed a double-blind
transplant patients with a cholesterol concentration randomized controlled trial of intravenous ciclosporin
below 3.1 mM [33]. It is hypothesized that lower 4 mg/kg as monotherapy in hospital inpatients with
cholesterol levels increase the amount of ciclosporin severe colitis [39]. Most had not received cortico-
bound to low-density lipoprotein particles, resulting in steroids prior to trial entry. Fifteen patients received
increased delivery of ciclosporin to astrocytes, (which ciclosporin and 64% responded after 8 days, compared
have low-density lipoprotein receptors) [34]. There to 53% of the 15 patients who received intravenous
would need to be disruption of the blood–brain barrier methylprednisolone 40 mg daily. No major toxicity was
to allow this, and this may explain the increased seen. Responders were converted to oral therapy. Non-
neurotoxicity seen in liver transplant patients receiving responders were given combination therapy, with one
ciclosporin. Consequently, it is recommended that out of three ciclosporin non-responders improving and
colitis patients do not receive ciclosporin if the choles- three of seven methylprednisolone non-responders im-
terol is below 3 mM [11], and hypomagnesaemia should proving. Combination therapy still seems likely to be
be corrected prior to treatment. more effective, but monotherapy with ciclosporin may
be safer. After 1 year, seven of nine (78%) initially
Dose and route of administration controlled with ciclosporin remained in remission,
The most widely used dose of ciclosporin remains compared to three of eight (37%) controlled on methyl-
4 mg/kg/day by continuous intravenous infusion, based prednisolone. Unfortunately, far fewer patients in the
on the placebo controlled trial [10]. This would typi- corticosteroid group were put on azathioprine, so long-
cally produce ciclosporin levels of 300–500 ng/ml. The term results cannot be compared.
majority of side effects are dose dependent, and there
is considerable interest in using lower doses, with the Ciclosporin enemas
possibility of improved risk/benefit ratios. In colitis, In spite of early promise, ciclosporin enemas have been
suitable target levels to induce remission are not shown to be ineffective in a placebo controlled study in
known, but in responders on oral medication, clinicians 40 patients with left-sided colitis [40].

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
242 European Journal of Gastroenterology & Hepatology 2003, Vol 15 No 3

Table 2 Safe use of ciclosporin in refractory colitis

Pre-treatment Contra-indications
• Counsel patient regarding risks/benefits • Pregnancy
• Check blood pressure • Hypertension
• Cholesterol (if , 3 mM, increased risk of neurotoxicity) • Renal impairment
• Magnesium (correct if , 0.60 mM) • Poor general condition
• Renal function • Epilepsy
• LFT • Long-standing pan-colitis or colonic dysplasia

Treatment schedule
• Dose: 4 mg/kg/day by continuous infusion is standard. Consider 2 mg/kg/day or oral microemulsion 5 mg/kg/day in b.d. dosage
• Consider Pneumocystis prophylaxis with co-trimoxazole if on high-dose corticosteroids
• Discontinue if no response in 7 days
• In responders:
(1) Aim for trough level of 100–200 ng/ml
(2) Add purine analogue unless intolerant
(3) Measure K, creatinine, Mg, LFT and blood pressure regularly
(4) Tail off gradually after 3–6 months

Drug interactions
Increase ciclosporin levels Increase risk of nephrotoxicity
Grapefruit juice Aminoglycosides
Erythromycin/clarithromycin Co-trimoxazole/trimethoprim
Itraconazole/ketoconazole Quinolones
Fluconazole/miconazole Amphotericin
Ursodeoxycholic acid
Diltiazem/nicardipine/verapamil
High-dose methylprednisolone Reduce ciclosporin levels
Danazol Rifampicin
Progestogens St John’s wort
Cimetidine Carbamazepine/phenytoin/phenobarbitone
Ticlopidine

LFT, liver function test.

Ciclosporin or surgery? in surgical complications after failed ciclosporin [41–

Patients with refractory colitis face a stark choice 43], although whether this is true of experience outside
between prompt surgery and ciclosporin therapy. Ciclo- specialist centres is unknown. A case of post-operative
sporin presents no easy option and should not delay Pneumocystis carinii pneumonia has been reported [44].
appropriate surgery. It should be remembered that the
mortality from severe ulcerative colitis, including those
who come to surgery, has declined from more than 30% Future directions
to ,1% in specialist centres in the past 40 years [1]. High short-term response rates will ensure that ciclo-
Only one or two patients need to die as a result of sporin will continue to be used as a rescue therapy in
ciclosporin (or any other therapy) to question a change corticosteroid refractory colitis. The longer-term results
in therapeutic approach. Patients being considered for are less encouraging, but have to be seen in context.
ciclosporin must be counselled about toxicity, the need These patients would otherwise have undergone colect-
for ongoing immunosuppression, and close follow-up, omy and a long-term remission rate of 30–40% is better
often over many months. In spite of the risks, and than is achieved with infliximab therapy for refractory
inconvenience, most patients do opt for ciclosporin, and Crohn’s disease. Careful selection and monitoring of
the quality of life in responders has been reported to patients (Table 2), use of lower doses, and oral therapy
be better than in those who have undergone colectomy will all help to reduce side effects.
[17]. The message must be that, if ciclosporin is consid-
ered, it must be considered at an early stage. One
approach is to use the 3 day predictive index of the Annotated references
d
Of special interest
stool frequency and C-reactive protein (C-reactive dd
Of outstanding interest
protein .45 mg/l or a stool frequency .8/day after
1 Travis SPL, Farrant JM, Ricketts C, Nolan DJ, Mortensen NM, Kettlewell
3 days’ intensive treatment is associated with colectomy MG, Jewell DP. Predicting outcome in severe ulcerative colitis. Gut
in 85% [1]), but this has not been subjected to a 1996; 38:905–910.
controlled trial. Failure to respond after 7 days of 2 Atkinson KA, McDonald JW, Lamba B, Feagan BG. Intravenous cyclo-
sporine for severe attacks of ulcerative colitis: a survey of Canadian
ciclosporin should be an absolute indication for surgery. gastroenterologists. Can J Gastroenterol 1997; 11:583–587.
It is encouraging that several studies show no increase 3 Stack WA, Williams D, Stevenson M, Logan RF. Immunosuppressive

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Review in depth Ciclosporin and refractory colitis Hawthorne 243

therapy for ulcerative colitis: results of a nation-wide survey among gui CS, et al. Calcium channel blockers protect transplant patients from
consultant physician members of the British Society of Gastroenterol- cyclosporine-induced daily renal hypoperfusion. Kidney Int 1993;
ogy. Aliment Pharmacol Ther 1999; 13:569–575. 43:706–711.
4 Meuwissen SG, Ewe K, Gassull MA, Geboes K, Jewell D, Pallone F, et 25 Mihatsch MJ, Ryffel B, Gudat F, Thiel G. Cyclosporine nephropathy. In:
al. IOIBD questionnaire on the clinical use of azathioprine, 6-mercapto- Tisher CC, Brenner BM (editors). Renal Pathology: with Clinical and
purine, cyclosporin A and methotrexate in the treatment of inflammatory Functional Correlations. 2nd edition. Philadelphia: Lippincott; 1994,
bowel diseases. Eur J Gastroenterol Hepatol 2000; 12:13–18. pp. 1641–1681.
5 Timmerman LA, Clipstone NA, Ho SN, Northrop JP, Crabtree GR. 26 Quan VA, Sauders BP, Hicks BH, Sladen GE. Cyclosporin treatment
Rapid shuttling of NF-AT in discrimination of Caþþ signals and immuno- for ulcerative colitis complicated by fatal Pneumocystis carinii pneumo-
suppression. Nature 1996; 383:837–840. nia. BMJ 1997; 314:363–364.
6 Wiederrecht G, Lam E, Hung S, Martin M, Sigal N. The mechanism of 27 Stack WA, Richardson PD, Logan RPH, Mahida YR, Hawkey CJ.
action of FK-506 and cyclosporin A. Ann NY Acad Sci 1993; 696: Nocardia asteroides lung abscess in acute ulcerative colitis treated
9–19. with cyclosporine. Am J Gastroenterol 2001; 96:2255–2256.
7 Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immuno- 28 Caroli A, Fregoese D, Di Falco G, D’Inca R. Aspergillus fumigatus
pharmacology 2000; 47:119–125. pneumonia during cyclosporine treatment for ulcerative colitis. Am J
8 Kim WU, Cho ML, Kim SI, Yoo WH, Lee SS, Joo YS, et al. Divergent Gastroenterol 2000; 95:3016–3017.
effect of cyclosporine on Th1/Th2 type cytokines in patients with 29 Vega R, Bertran X, Menacho M, Domenech E, Moreno de Vega V,
severe, refractory rheumatoid arthritis. J Rheumatol 2000; 27: Hombrados M, et al. Cytomegalovirus infection in patients with
324–331. inflammatory bowel disease. Am J Gastroenterol 1999; 94:
9 Gupta S, Keshavarzian A, Hodgson HJF. Cyclosporin in ulcerative 1053–1056.
colitis. Lancet 1984; ii:1277–1278. 30 Humphreys TR, Leyden JJ. Acute reversible central nervous system
dd
10 Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, et al. toxicity associated with low-dose oral cyclosporine therapy. J Am Acad
Cyclosporine in severe ulcerative colitis refractory to steroid therapy. Dermatol 1993; 29:490–492.
N Engl J Med 1994; 330:1841–1845. 31 Durrant S, Chipping PM, Palmer S, Gordon-Smith EC. Cyclosporin A,
Randomized controlled trial of intravenous ciclosporin infusion versus placebo in methylprednisolone, and convulsions. Lancet 1982; ii:829–830.
patients failing 7 days of intravenous steroids. Dramatic short-term benefit, with 32 Thompson CB, June CH, Sullivan KM, Thomas ED. Association be-
82% response on ciclosporin, versus no response on placebo. This small trial tween cyclosporin neurotoxicity and hypomagnesaemia. Lancet 1984;
established intravenous infusion of 4 mg/kg/day as the dose of choice. ii:1116–1120.
11d Kornbluth A, Present DH, Lichtiger S, Hanauer S. Cyclosporin for 33 De Groen PC, Aksamit AJ, Rakela J, Gorbes GS, Krom RAF. Central
severe ulcerative colitis: a user’s guide. Am J Gastroenterol 1997; nervous system toxicity after liver transplantation. N Engl J Med 1987;
92:1424–1428. 317:861–866.
Practical information about how to administer ciclosporin safely, and recommen- 34 De Groen PC. Cyclosporine, low-density lipoprotein, and cholesterol.
dations for screening and monitoring patients. Mayo Clin Proc 1988; 63:1012–1021.
12 Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative 35 Hemming AAW, Greig PD, Cattral MS, Chung SW, Lilly LB, Aljumah
colitis: a five-year experience. Am J Gastroenterol 1999; 94: AA, et al. A microemulsion of cyclosporine without intravenous cyclo-
1587–1592. sporine in liver transplantation. Transplantation 1996; 62:1798–1802.
13 Fernandez-Benares F, Bertran X, Esteve-Comas M, Cabre E, Menacho 36 Actis GC, Volpes R, Rizzetto M. Oral microemulsion cyclosporin to
M, Humbert P, et al. Azathioprine is useful in maintaining long-term reduce steroids rapidly in chronic active ulcerative colitis. Eur J
remission induced by intravenous cyclosporine in steroid-refractory Gastroenterol Hepatol 1999; 11:905–908.
severe ulcerative colitis. Am J Gastroenterol 1996; 91:2498–2499. 37 Oppong K, Record CO. Neoral may be as effective as intravenous
14 Actis GC, Bresso F, Astegiano M, Demarchi B, Sapone N, Boscaglia cyclosporine in the treatment of steroid-resistant ulcerative colitis. Am J
C, et al. Safety and efficacy of azathioprine in the maintenance of Gastroenterol 1998; 93:1188–1189.
cyclosporin-induced remission of ulcerative colitis. Aliment Pharmacol 38 Van Assche G, D’Haens G, Noman M, Hiele M, Asnong K, Aerden I, et
Ther 2001; 15:131–137. al. Randomized double blind comparison of 4 mg/kg versus 2 mg/kg IV
15 Ramakrishna J, Langhans N, Calenda K, Grand RJ, Verhave M. Com- cyclosporine in severe ulcerative colitis. Gastroenterology 2002;
bined use of cyclosporine and azathioprine or 6-mercaptopurine in 122:A81.
dd
pediatric inflammatory bowel disease. J Ped Gastroenterol Nutr 1996; 39 D’Haens G, Lemmens L, Geboes K, Candeputte L, Van Acker F,
22:296–302. Mortelmans L, et al. Intravenous cyclosporine versus intravenous
16 Haslam N, Hearing SD, Probert CSJ. Audit of cyclosporin use in corticosteroids as single therapy for severe attacks of ulcerative colitis.
inflammatory bowel disease: limited benefits, numerous side-effects. Gastroenterology 2001; 120:1323–1329.
Eur J Gastroenterol Hepatol 2000; 12:657–660. A randomized trial showing that monotherapy with i.v. ciclosporin is as effective
17 Cohen RD, Brodsky AL, Hanauer SB. A comparison of the quality of as i.v. methylprednisolone. Forty per cent of non-responders to either therapy
life in patients with severe ulcerative colitis after total colectomy versus alone improved on combined treatment. There was no severe toxicity in the
medical treatment with intravenous cyclosporin. Inflamm Bowel Dis ciclosporin group, and treatment without corticosteroids may be safer, but
1999; 5:1–10. combined therapy still seems more effective.
18 Rowe FA, Walker JH, Karp LC, Vasiliauskas EA, Plevy SE, Targan SR. 40d Sandborn WJ, Tremaine WJ, Schroeder KW, Batts KP, Lawson GM,
Factors predictive of response to cyclosporin treatment for severe, Steiner BL, et al. A placebo-controlled trial of cyclosporine enemas for
steroid-resistant ulcerative colitis. Am J Gastroenterol 2000; 95: mildly to moderately active left-sided ulcerative colitis. Gastroenterology
2000–2008. 1994; 106:1429–1435.
19 Santos J, Baudet S, Casellas F, Guarner L, Vilaseca J, Malagelada J-R. Ciclosporin enemas are ineffective in distal colitis.
Efficacy of intravenous cyclosporin for steroid refractory attacks of 41 Fleshner PR, Michelassi F, Rubin M, Hanauer SB, Plevy SE, Targan
ulcerative colitis. J Clin Gastroenterol 1995; 20:285–289. SR. Morbidity of subtotal colectomy in patients with severe ulcerative
20 Stack WA, Long RG, Hawkey CJ. Short- and long-term outcome of colitis unresponsive to ciclosporin. Dis Colon Rectum 1995; 38:
patients treated with cyclosporin for severe acute ulcerative colitis. 1241–1245.
Aliment Pharmacol Ther 1998; 12:973–978. 42 Pinna-Porter M, Arese P, Bona R, Falletto E, Schieroni R, Villata E,
21 Carbonnel F, Boruchowicz A, Duclos B, Soule JC, Lerebours E, Leman et al. Severe steroid-unresponsive ulcerative colitis. Outcomes of
M, et al. Intravenous cyclosporine in attacks of ulcerative colitis. Short- restorative proctocolectomy in patients undergoing cyclosporin treat-
term and long-term responses. Dig Dis Sci 1996; 41:2471–2476. ment. Dis Colon Rectum 2000; 43:609–614.
22d Actis GC, Aimo G, Priolo G, Moscato D, Rizzetto M, Pagni R. Efficacy 43 Hyde GM, Jewell DP, Kettlewell MGW, Mortensen NJMcC. Cyclosporin
and efficiency of oral microemulsion cyclosporin versus intravenous for severe ulcerative colitis does not increase the rate of perioperative
and soft gelatin capsule cyclosporin in the treatment of severe steroid- complications. Dis Colon Rectum 2001; 44:1436–1440.
refractory ulcerative colitis: an open-label retrospective trial. Inflamm 44 Scott AM, Myers GA, Harms BA. Pneumocystis carinii pneumonia
Bowel Dis 1998; 4:276–279. post-restorative proctocolectomy for ulcerative colitis: a role for peri-
Large series of patients receiving low-dose intravenous or oral ciclosporin. operative prophylaxis in the cyclosporine era? Report of a case and
23 Lanese DM, Conger JD. Effect of endothelin receptor antagonist on review of the literature. Dis Colon Rectum 1997; 40:973–976.
cyclosporine-induced vasoconstriction in isolated rat renal arterioles. 45 Lichtiger S, Present DH. Preliminary report: cyclosporin in treatment of
J Clin Invest 1993; 91:2144–2149. severe active ulcerative colitis. Lancet 1990; 336:16–19.
24 Ruggenenti P, Perico N, Mosconi L, Gaspari F, Benigni A, Amuchaste- 46 Van Gossum A, Schmit A, Adler M, Chioccioli C, Fiasse R, Louwagie

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
244 European Journal of Gastroenterology & Hepatology 2003, Vol 15 No 3

P, et al. Short- and long-term efficacy of cyclosporin administration in

patients with acute severe ulcerative colitis. Acta Gastroenterol Belg
1997; 60:197–200.
47 Wenzl HH, Petritsch W, Aichbichler BW, Hinterleitner TA, Fleischmann
G, Krejs GJ. Short-term efficacy and long-term outcome of cyclosporine
treatment in patients with severe ulcerative colitis. Z Gastroenterol
1998; 36:287–293.
48d Hyde GM, Thillainayagam AV, Jewell DP. Intravenous cyclosporin as
rescue therapy in severe ulcerative colitis: time for a reappraisal? Eur J
Gastroenterol Hepatol 1998; 10:411–413.
Survey of ciclosporin use in 50 patients with 56% short-term and 40% long-
term response (mean 19 months).
49 Hermida-Rodriguez C, Cantero Perona J, Garcia-Valriberas R, Pajares
Garcia JM, Mate-Jimenez J. High-dose intravenous cyclosporine in
steroid refractory attacks of inflammatory bowel disease. Hepatogas-
troenterology 1999; 46:2265–2268.
50 Treem WR, Cohen J, Davis PM, Justinich CJ, Hyams JS. Cyclosporine
for the treatment of fulminant ulcerative colitis in children. Immediate
response, long-term results, and impact on surgery. Dis Colon Rectum
1995; 38:474–479.
51 Navazo L, Salata H, Morales S, Dorta MC, Perez F, de las Casas D,
Aviles J. Oral microemulsion cyclosporine in the treatment of steroid-
refractory attacks of ulcerative and indeterminate colitis. Scand J
Gastroenterol 2001; 36:610–614.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.