Review in depth 239
Ciclosporin and refractory colitis
A. Barney Hawthorne
Intravenous ciclosporin 4 mg/kg daily is rapidly effective
as a salvage therapy for patients with refractory colitis,
who would otherwise face colectomy, but its use is
controversial because of risk of toxicity, and long-term
failure rate. Opportunistic infections remain a serious
concern, with a number of reports of death related to
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ciclosporin. Renal and neurotoxicity are also well-
recognized. The drug should not be continued for more
than 3–6 months and its main role is as a bridge to
azathioprine or 6-mercaptopurine. Risks of toxicity can be
reduced by using lower doses (2 mg/kg/day
intravenously), by oral microemulsion ciclosporin, or by
monotherapy without corticosteroids. Preliminary evidence
Introduction
Treatment with intravenous corticosteroids remains the
mainstay of treatment in hospital for severe ulcerative
colitis, but the colectomy rate for treatment failure is
about 30% [1]. These figures have not changed sub-
stantially over the past 40 years. Most patients are
desperate to avoid surgery, because of the need for an
ileostomy. Although an ileo-anal pouch procedure can
remove the need for long-term ileostomy, it rarely
restores bowel function to normality. Patients are
usually keen to pursue intensive medical therapy to
avoid surgery. The use of ciclosporin as a rescue
therapy in severe colitis is the only significant advance
in medical therapy since the introduction of intra-
venous corticosteroids, yet the role of this drug remains
controversial, with doubts about side effects and long-
term outcomes. A survey reported in 1997 showed that
only 26% of Canadian gastroenterologists used ciclo-
sporin [2]. More recent surveys have shown the drug is
used by just under half of gastroenterologists in the UK
[3], USA and Europe [4], and only in very small
numbers of patients.
Mode of action
In 1970, a researcher at Sandoz Inc. collected soil
samples during his summer holiday. After his return to
work, the microbiology department isolated a new
strain of fungus (Tolypocladium inflatum Gams) and,
from this, a peptide was isolated with potent immuno-
suppressive, but no myelotoxic activity. Ciclosporin is a
lipophilic cyclic undecapeptide that binds with high
affinity to its cytoplasmic receptor protein cyclophilin.
The ciclosporin–cyclophilin complex specifically and
competitively binds to and inhibits calcineurin, a cal-
cium and calmodulin dependent phosphatase. This
0954-691X & 2003 Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
shows good response rates, but further studies are
needed to confirm optimal use of this potent, but
hazardous, therapy. Eur J Gastroenterol Hepatol 15:239–
244 & 2003 Lippincott Williams & Wilkins
European Journal of Gastroenterology & Hepatology 2003, 15:239–244
Keywords: ulcerative colitis, ciclosporin, immunosuppressive agents
Department of Medicine, University Hospital of Wales, Cardiff, UK.
Correspondence to Dr A. Barney Hawthorne, Department of Medicine, University
Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK.
Tel: +44 (0)29 2074 2183; fax: +44 (0)29 2074 5131;
e-mail: Barney.Hawthorne@UHW-TR.wales.nhs.uk
prevents translocation of a family of transcription
factors, nuclear factor activated T cells (NF-AT) [5],
which reduces activation of genes for interleukin (IL)-
2, IL-3, IL-4, granulocyte macrophage colony-stimulat-
ing factor, tumour necrosis factor alpha and interferon
gamma [6]. T-cell transcription factors AP-1 and NF-
kB are also inhibited [7]. Ciclosporin acts predomi-
nantly on CD4 cells, and in rheumatoid arthritis there
is a shift from Th1 to Th2 type cytokine expression [8].
Clinical evidence of benefit
The first report of ciclosporin use in ulcerative colitis
was published in 1984 [9]. The use of ciclosporin
became more widespread after publication of a small
placebo controlled trial from Chicago and New York by
Lichtiger and colleagues [10]. This study randomized
20 hospital inpatients with severe colitis unresponsive
to 7 days of intravenous corticosteroids, to receive
ciclosporin 4 mg/kg daily by continuous intravenous
infusion, or placebo. Nine of 11 patients receiving
active drug had improvement within days, while none
of the placebo group improved. Although the trial was
very small, and did not include sigmoidoscopic assess-
ment, it established that ciclosporin worked quickly,
and could produce high response rates in the short
term, for patients who would otherwise undergo colect-
omy. The trial established the intravenous infusion of
4 mg/kg/day as the standard dose, and the same authors
published practical guidelines on ciclosporin usage [11].
Although no other placebo controlled studies have been
published, there have been many uncontrolled reports
of ciclosporin use in refractory colitis, and these are
summarized in Table 1. These studies provide support
for the high short-term response rates, with a mean
DOI: 10.1097/01.meg.0000049996.68425.4f
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-
tion) of 73%. These reports showed, however, that the
medium-and long-term response rates were much low-
er. Just less than half the patients (47%) avoided
colectomy in those studies reporting follow-up for more
than a year. This is still an appreciable proportion, but
ciclosporin is clearly not a cure for colitis. Long-term
remission is more likely if patients are treated with
azathioprine or 6-mercaptopurine [12,13]. Combination
therapy does not seem to increase the risk of toxicity
[14,15], although caution is necessary (see below). It
seems logical to use oral microemulsion ciclosporin for
3–6 months as a bridge to purine analogue therapy.
Many questions remain about the use of ciclosporin in
refractory colitis. These include the risk of major side
effects and whether the long-term success rate in
avoidance of colectomy or achieving remission off
corticosteroids can justify the considerable risks. The
optimal dose, route of delivery and duration of therapy
remain to be clarified. These questions have to be
considered in the context of the possibility that safer
drugs will supersede ciclosporin.
Toxicity
In published case series, the risk of minor side effects
ranges from 31% to 51% [16–18], including tremor,
paraesthesiae, malaise, headache, abnormal liver func-
tion, gingival hyperplasia and hirsutism. Major compli-
cations are reported with a frequency from 0% to 17%
[17–22], including renal, infectious and neurotoxic
effects.
Mild, reversible renal impairment in colitis patients
treated with ciclosporin is common. There are only
isolated reports of serious renal failure (such as acute
renal failure [16], which in this case was reversible),
probably because of the short duration of therapy.
Acute nephrotoxicity is due to a dose dependent
vasoconstriction of afferent and efferent glomerular
arterioles, resulting in reduced renal blood flow and a
fall in glomerular filtration rate [23]. The effect can be
reduced by treatment with calcium channel blockers
[24], but may be increased by the concomitant prescrip-
tion of other nephrotoxic drugs. A rare effect of
ciclosporin is a vascular lesion akin to that in haemoly-
tic–uraemic syndrome. This is idiosyncratic and leads
to irreversible renal failure. Chronic nephrotoxicity [25]
results from obliterative arteriolopathy, ischaemic col-
lapse or scarring of glomeruli, vacuolization of tubules,
and focal tubular atrophy and interstitial fibrosis. A
fourth renal problem is tubular dysfunction, resulting in
hyperuricaemia, metabolic acidosis, hypophosphataemia
and hypomagnesaemia.
Infections
The profound immunosuppressive effects of ciclosporin
result in a significant risk of infections. The risk is dose
dependent and compounded by co-treatment with
corticosteroids, and the general condition of the patient.
Infective complications reported include opportunistic
pathogens, particularly Pneumocystis carinii [17–19,26],
but also Nocardia sp. lung abscess [27], Aspergillus
fumigatus pneumonia [28], Listeria monocytogenes menin-
gitis [16], cytomegalovirus, herpes simplex anal ulcers
and Candida infections [18,29]. Septicaemia from con-

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

ventional infections also occurs, such as Staphylococcus
aureus and Haemophilus influenzae [21]. Deaths are
reported in a number of series or case reports, and
are usually due to overwhelming infection [19,22,26].
Pneumocystis prophylaxis with co-trimoxazole should be
considered if patients are also on high-dose cortico-
steroids, noting that this can also cause a modest rise in
creatinine. It cannot, however, be stipulated because
unlike transplant patients, the pre-morbid health of the
individual has usually been good, the duration of
therapy is short and most opportunistic infections will
not be covered by co-trimoxazole. Additional caution is
necessary, because interaction between co-trimoxazole
and azathioprine to cause bone marrow suppression is
predictable.
Neurotoxicity
Minor neurotoxic effects of ciclosporin include tremor,
burning paraesthesiae, headaches, blurred vision and
malaise. More serious effects include seizures, coma,
spasticity, ataxia, and many other effects [30]. Mechan-
isms are uncertain, but ciclosporin in rats reduces
seizure threshold. The drug is highly lipophilic, binds
to serum lipids, and readily penetrates the blood–brain
barrier. Magnetic resonance scanning suggests axonal
swelling, and reversible ischaemia may result from
vasoconstriction. These effects are dose related, and
reversible, but they can occur at low doses [30] and the
risk of neurotoxicity may be increased by many factors,
including high-dose corticosteroids [31], hypertension,
and hypomagnesaemia [32]. In transplant patients, low
serum cholesterol predisposes to seizures and neuro-
toxicity. In one study, toxicity only occurred in liver
transplant patients with a cholesterol concentration
below 3.1 mM [33]. It is hypothesized that lower
cholesterol levels increase the amount of ciclosporin
bound to low-density lipoprotein particles, resulting in
increased delivery of ciclosporin to astrocytes, (which
have low-density lipoprotein receptors) [34]. There
would need to be disruption of the blood–brain barrier
to allow this, and this may explain the increased
neurotoxicity seen in liver transplant patients receiving
ciclosporin. Consequently, it is recommended that
colitis patients do not receive ciclosporin if the choles-
terol is below 3 mM [11], and hypomagnesaemia should
be corrected prior to treatment.
Dose and route of administration
The most widely used dose of ciclosporin remains
4 mg/kg/day by continuous intravenous infusion, based
on the placebo controlled trial [10]. This would typi-
cally produce ciclosporin levels of 300–500 ng/ml. The
majority of side effects are dose dependent, and there
is considerable interest in using lower doses, with the
possibility of improved risk/benefit ratios. In colitis,
suitable target levels to induce remission are not
known, but in responders on oral medication, clinicians
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Review in depth Ciclosporin and refractory colitis Hawthorne 241
generally aim for whole-blood trough levels of 100–
200 ng/ml using a monoclonal radioimmunoassay.
Oral treatment
The microemulsion based formulation of ciclosporin
was developed to overcome problems of poor and
unpredictable absorption of the standard oral prepara-
tion. Oral microemulsion ciclosporin is now used widely
to initiate immunosuppression after organ transplanta-
tion [35]. An oral dose of 5 mg/kg/day would be equiva-
lent to 2 mg/kg/day intravenously [36]. There are
reports of use of oral ciclosporin [37], and Actis and
colleagues have published case series [22,36] reporting
good responses to both intravenous doses of 2 mg/kg
and oral 5 mg/kg daily, without serious side effects.
Table 1 shows that there is a wide range of initial
response rates to 4 mg/kg, or more, given daily by the
intravenous route, with a mean response rate of 73%. A
lower intravenous dose, or oral dose regimens compare
favourably with this. Clearly these trials (Table 1) are
widely different, and may have used very different
criteria in patient selection for ciclosporin, but raise the
hope that lower doses may be equally effective. This is
borne out by a recent randomized controlled trial in 70
patients, published in abstract form [38] from Leuven,
Belgium, showing that patients receiving 2 mg/kg intra-
venously had an 85% response rate at 3 months, which
was similar to the response rate of 82% on 4 mg/kg.
Monotherapy
Other strategies to reduce the toxicity of ciclosporin
include its use as monotherapy without corticosteroids.
The Leuven group have performed a double-blind
randomized controlled trial of intravenous ciclosporin
4 mg/kg as monotherapy in hospital inpatients with
severe colitis [39]. Most had not received cortico-
steroids prior to trial entry. Fifteen patients received
ciclosporin and 64% responded after 8 days, compared
to 53% of the 15 patients who received intravenous
methylprednisolone 40 mg daily. No major toxicity was
seen. Responders were converted to oral therapy. Non-
responders were given combination therapy, with one
out of three ciclosporin non-responders improving and
three of seven methylprednisolone non-responders im-
proving. Combination therapy still seems likely to be
more effective, but monotherapy with ciclosporin may
be safer. After 1 year, seven of nine (78%) initially
controlled with ciclosporin remained in remission,
compared to three of eight (37%) controlled on methyl-
prednisolone. Unfortunately, far fewer patients in the
corticosteroid group were put on azathioprine, so long-
term results cannot be compared.
Ciclosporin enemas
In spite of early promise, ciclosporin enemas have been
shown to be ineffective in a placebo controlled study in
40 patients with left-sided colitis [40].
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
between prompt surgery and ciclosporin therapy. Ciclo-
sporin presents no easy option and should not delay
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%
to ,1% in specialist centres in the past 40 years [1].
Only one or two patients need to die as a result of
ciclosporin (or any other therapy) to question a change
in therapeutic approach. Patients being considered for
ciclosporin must be counselled about toxicity, the need
for ongoing immunosuppression, and close follow-up,
often over many months. In spite of the risks, and
inconvenience, most patients do opt for ciclosporin, and
the quality of life in responders has been reported to
be better than in those who have undergone colectomy
[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
stool frequency and C-reactive protein (C-reactive
protein .45 mg/l or a stool frequency .8/day after
3 days’ intensive treatment is associated with colectomy
in 85% [1]), but this has not been subjected to a
controlled trial. Failure to respond after 7 days of
ciclosporin should be an absolute indication for surgery.
It is encouraging that several studies show no increase
43], although whether this is true of experience outside
specialist centres is unknown. A case of post-operative
Pneumocystis carinii pneumonia has been reported [44].
Future directions
High short-term response rates will ensure that ciclo-
sporin will continue to be used as a rescue therapy in
corticosteroid refractory colitis. The longer-term results
are less encouraging, but have to be seen in context.
These patients would otherwise have undergone colect-
omy and a long-term remission rate of 30–40% is better
than is achieved with infliximab therapy for refractory
Crohn’s disease. Careful selection and monitoring of
patients (Table 2), use of lower doses, and oral therapy
will all help to reduce side effects.
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Of special interest
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