A placebo-controlled trial of cyclosporine enemas for mildly to moderately active left-sided ulcerative colitis

A Placebo-Controlled Trial of Cyclosporine Enemas for Mildly to Moderately Active Left-Sided Ulcerative Colitis WILLIAM J. SANDBORN,* WILLIAM J. TREMAINE,* KENNETH W. SCHROEDER,* KENNETH P. BATTS,? GEORGE M. LAWSON,’ BETTY L. STEINER,* JAY M. HARRISON,” and ALAN R. ZINSMEISTER5 *Inflammatory Bowel Disease Clinic, Division of Gastroenterology, ‘Department Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

Background/Aims: Uncontrolled studies suggest that cyclosporine administered as an enema may be of benefit for left-sided ulcerative colitis and safer than intravenous or oral administration. The efficacy and safety of cyclosporine enemas for left-sided ulcerative colitis in a placebo-controlled trial was assessed. Methods: Steroid and mesalamine enemas were withdrawn be fore the study. Forty patients were assigned to 1 of 4 strata: no concomitant therapy, oral steroids, oral salicylates, or oral steroids and salicylates. After stratification, patients were randomized to nightly treatment with 350 mg cyclosporine (n = 20) or placebo (n = 20) enemas. Clinical response was determined at baseline and 4 weeks by endoscopy, physician assessment, and a patient diary of daily symptoms. Trough blood cyclosporine levels were measured by high-performance liquid chromatography. Results: At 4 weeks, 8 of 20 patients (40%) who received cyclosporine showed clinical improvement compared with 9 of 20 patients (45%) who received placebo. One patient receiving cyclosporine had reversible neutropenia attrib utable to sulfasalazine, and another patient receiving cyclosporine was unable to tolerate the enema vehicle. No other toxicity was noted during the trial. Blood cyclosporine levels were detectable in only two patients. Conclusions: Cyclosporine enemas administered in a dosage of 350 mg/day for 4 weeks are not efficacious in mildly to moderately active left-sided ulcerative colitis.

of Laboratory Medicine and Pathology, *Section of

toxicity

cyclosporine

treatment

C

is a cyclic endecapeptide

that has revolu-

tionized solid organ transplantation because of its unique ability to selectively inhibit cellular immunity.’ Multiple uncontrolled studies have suggested that cyclosporine administered orally or intravenously is of benefit in patients with severe ulcerative colitis who are refractory to standard therapy.2-‘7 Two controlled trials of oral or intravenous cyclosporine in patients with mildly to moderately active18 and severely activer” ulcerative colitis have confirmed these observations. Serious,

oral

and

of inflammatory

intravenous

bowel disease has

been minimal,

but there is a high incidence of cyclosporexperience with side effects.20 Furthermore,

ine-related cyclosporine

in other settings,

such as organ transplanta-

tion, has shown that serious toxicity In an attempt avoiding

to reduce

can occur.

cyclosporine

small bowel absorption,

side effects by

cyclosporine

has been

administered as an enema. We have previously reported a pharmacokinetic study showing that blood concentrations are negligible

and colonic

tissue concentrations

are

quite high after enema administration of cyclosporine.21 Four uncontrolled studies of cyclosporine enema treatment

for patients

with

left-sided

ulcerative

colitis

have

reported response rates ranging from 50% - 7 5 % .22-26 No side effects attributable to cyclosporine have been reported

after enema administration.

sults of a 4-week (350 mg/day)

controlled

in patients

We report

trial of cyclosporine

with active left-sided

the reenemas

ulcerative

colitis.

Materials Study

and Methods

Design

This study was a randomized, double-blind, placebocontrolled trial using 350 mg/day ofcyclosporine administered as an enema in patients with mildly to moderately active leftsided ulcerative colitis. Patients were assigned to 1 of 4 strata based on treatment

yclosporine

during

irreversible

no treatment, olsalazine, roids,

with

oral mesalamine),

or treatment

Patients

at the time of enrollment

treatment with

were not stratified

oral salicylates treatment

oral salicylates

with

into the study: (sulfasalatine, oral corticoste-

and corticosteroids.

for topical therapy (topical cortico-

steroids or mesalamine) because these medications were discontinued before beginning the study medication for reasons discussed within

below. To maintain a balance of treatment groups each stratum, randomization was performed separately

0 1994 by the American Gastroenterological Association 00165085/94/$3.00

GASTROENTEROLOGY Vol. 106, No. 6

1430

SANDBORN ET AL.

within

each of the four strata using a randomization

developed

sequence

in the Section of Biostatistics.

Patients From September patients

with mildly

1991 to November

to moderately

colitis were referred by colleagues

1992, 40 adult

active left-sided

ulcerative

at the Mayo Clinic for enroll-

ment into the study. Active ulcerative

colitis was diagnosed

the usual symptomatic,

and endoscopic

criteria.

disease were excluded

because

Patients

radiographic,

with newly diagnosed

we wished to study patients to standard tutional

treatment.27

Review

gave informed,

who tended

The study was approved

and/or

continued

at prestudy

been changed

during doses

studying topical

(sulfasalazine,

oral corticosteroids

corticosteroid

therapies

120

the previous >20

were

Corticosteroid at least

perrectal

medications.

During

to take metronidazole, azathioprine,

to avoid

1 week

ova and parasites,

were required

evaluations

or other investiexamination

Women

to have a negative

count,

chemistry

pregnancy

tients

with renal dysfunction >2X

a trough

whole

(serum (alkaline

normal)

nine levels were measured performance

blood

panel,

test

complete

and urinalysis.

creatinine

Pa-

> 1.5X

phosphatase

nor-

or aspartate

were excluded.

Serum creati-

after 2 weeks of treatment,

cyclospotine

concentration

liquid chromatography)

and

(by high-

was determined

Throughout

the study, patients

at the 4-

kept a daily record of

the number of their stools, any rectal bleeding,

their subjective

sense of well-being,

the degree of abdominal

discomfort,

any other symptoms

coinciding

sent adverse reactions. of

during the trial. Laboratory

screening

mal) or hepatic dysfunction aminotransferase

for

capable

at the initial and 4-week visits included

blood

Disease Activity Assessment

6-

a negative stool culture for enteric pathogens,

and asked to practice contraception

Index

Stool frequency 0, Normal number of stools for this patient 1, l-2 stools more than normal 2, 3-4 stools more than normal 3, 5 or more stools more than normal Rectal bleeding 0, No blood found 1, Streaks of blood with stool less than half the time 2, Obvious blood with stool most of the time 3, Blood alone passed Sigmoidoscopic findings 0, Normal or inactive disease 1, Mild disease (etythema, decreased vascular pattern, mild friability) 2, Moderate disease (marked erythema, absent vascular pattern, friability, erosions) 3, Severe disease (spontaneous bleeding, ulceration) Physician’s global assessment 0, Normal 1, Mild disease 2, Moderate disease 3, Severe disease

the study, patients

had a negative toxin.

Activity

before

oral cyclosporine,

methotrexate,

Clostridim difiile

and a negative conception

each patient

Disease

with retention

drugs.

Before entry,

Colitis

and mesalamine

difficulties

mercaptopurine,

were

receiving

excluded

were discontinued

were not allowed

mesala-

mg/day)

2 weeks. Patients

mg/day

the study to avoid potential

of multiple

gational

olsalazine,

(dose,

doses during the trial if the doses had not

severely ill patients.

entering

by the Insti-

and all patients

consent.

Oral salicylate compounds mine)

to be more refractory

Board of the Mayo Clinic, written

by

Table1. Ulcerative

Patients

and after 4 weeks according that

measured

findings,

stool

severe) reflected

endoscopic physical

findings,

findings

rectal

and pertinent

and performance

mesalamine

ment was determined

physician

at the 4-week visit and from patient

remission

and clinical

sigmoidoscopy. marcation

Left-sided

disease extent

between endoscopically

was defined

as a de-

inflamed and endoscopically

normal colonic mucosa located not more than 60 cm from the anal verge. If the demarcation

was at exactly 60 cm (as mea-

sured by a 60-cm flexible sigmoidoscope), normal

colonic

mucosa

the tip of the endoscope. between

endoscopically

tissue was >60 the study.

then endoscopically

had to be clearly visible Patients inflamed

in which

proximal

and endoscopically

normal

cm from the anal verge were excluded

Colonic

mucosal

biopsy

during

each endoscopy

to confirm

severity

of histological

inflammation,

Ionic tissue concentration

specimens

from

were obtained

the diagnosis, and determine

of cyclosporine.

to

the demarcation

assess the the co-

improvement

indices

such

as

criteria

and Baron et a12’

appearance, has been used

in other studies of oral mesalamine

week visit. The extent and severity of colonic mucosal involveat the initial and 4-week visits by flexible

mild,

symptoms,

ofTtuelove’s28

the degree of clinical activity

enemas.32-33 Adverse

(quiescent,

recorded

clinical

criteria for grading the sigmoidoscopic previously

endoscopic

(Table 1). The phy-

status. This disease activity

index, which was based on modifications for classifying

bleeding,

of disease activity the patient’s

at study entry

disease activity index

global assessment

sician’s global assessment moderate,

were evaluated

to a 12-point

frequency,

and physician’s

and

with therapy that might repre-

therapy3”-3’ and

events were evaluated

by a

diaries. Clinical

were defined

as a disease

activity index score of zero and a decrease in the disease activity index of at least three points, respectively. Histological disease activity was also assessed at study entry and after 4 weeks according to a four-point histological disease activity index (Table 2).22 Assessed features included the nature (polymorphonuclear vs. entirely mononuclear) and distribution (lamina propria vs. cryptal) of the inflammatory cell infiltrate as well as the degree of glandular destruction and/or ulceration. Endoscopic biopsy specimens were obtained from the site in the distal colon that appeared to have the most severe inflammatory change. The histological disease activity index score was determined by a single pathologist (K.P.B.) who was

CYCLOSPORINE ENEMAS FOR ULCERATIVE COLITIS

June 1994

Table 2. Histological

Disease

Activity Index

0, Normal (normocellular lamina propria, PMNs absent) 1, inactive chronic colitis (hypercellular lamina propria, PMNs absent) 2, Mild active chronic colitis (scant PMNs in lamina propria, occasional cryptitis but few crypt abscesses, minimal glandular destruction or ulceration) 3, Moderately active chronic colitis (moderate numbers of PMNs in lamina propria with ct-yptitis and crypt abscesses prominent, some glandular destruction) 4. Severely active chronic colitis (numerous PMNs with abundant cryptitis, crypt abscesses, extensive glandular destruction, ulceration may be prominent) PMN, polymorphonuclear

cyclosporine as previously described.‘s.2’-23 The last enema was taken approximately 15 hours before the biopsies were performed. The tissue samples from each patient were frozen at -20°C in a drop of Tissue Tek (Miles Inc., Diagnostic Division,

Elkhart,

thawed, stool,

rinsed

IN). At the time of assay, the samples were

in 0.9%

or cyclosporine

and weighed.

saline

(to remove

adherent

Cyclosporine

minutes.

any Tissue

was extracted

by placing

the tissue

and homogenizing

The samples were then assayed for cyclosporine

the same methodology

that

Tek,

to the surface of the tissue),

in 2 mL of 9:l acetonitrile/methanol

for 2 using

we use for the measurement

whole blood cyclosporine.3’-‘6 tions were expressed

leukocyte.

1431

Tissue cyclosporine

in nanograms

of

concentra-

per gram wet tissue.

Statistical Methods blinded

to patient

identification,

point

in time (entry

week), and clinical status. The slides were reviewed sitting

in a randomized

histological activity

fashion.

improvement

Histological

disease activity

remission

and

disease

in the histological

index of at least one point,

The treatment

at a single

were defined as a histological

index score of zero and a decrease

vs. 4-

respectively.

baseline

demographic

and histological

Treatment Patients

consisted

were instructed

to add 3.5 mL of blinded-study

cation to the enema vehicle and retain

retention

were recorded

Each enema vehicle was composed

(Ruger Chemical Co., Irvington, methylcellulose

(Spectrum

isoosmolar

and the carboxymethylcellulose

added

to suspend

The vehicle,

into individual

This

g of sorbitol described

Corp.,

dose of sorbitol

reported

(Sandimmune East Hanover,

oral solution;

olive oil, were each dispensed

that the cremophors

castor oil for intravenous

oxyethylated

oleic glycerides

to extract

Sandoz Phar-

NJ), and the placebo

oxyethylated potential

was dispensed

The active study medi-

in llO-mL

glass bottles. The blinded-study medications cebo) were not mixed with the vehicle until because of concern

brown

in cyclosporine concentrate

phthlate

study

(active vs. plajust before use

for the oral solution)

diethylhexyl

(poly-

and polyhave the

from the polyvinyl

chloride enema bottles into the solution. s* Compliance determined by review of the patient diaries.

was

Measurement of Colonic Tissue Cyclosporine Concentration We obtained four mucosal pinch biopsy specimens from the rectosigmoid colon during flexible sigmoidoscopy performed

at the

4-week

visit

group between

treatment

group

change

a difference,

for assay of colonic

tissue

time

in the disease tissue

was considered

activity

index

vs.

concentra-

significant. group

and 20 in

there was 75% power for de-

corresponding

group

vs.

and were used

cyclosporine

in the placebo-treated group,

change in

vs. not improved)

retention

P <0.05

20 patients

the cyclosporine-treated tecting

(improved

and colonic

tions. A two-tailed With

index

and enema

separately

to 80%

compared

improvement

in

with 40% improvement

in

test at a type I error rate

of 5%.

Results

is well

to cause a cathartic

previously,*i~**

100-mL enema bottles.

cation, cyclosporine medication,

Corp.,

the vehicle

cyclosporine.

activity

NJ), and 500 mg carboxyto make

improvement,

rank tests or extensions Logistic regression

the placebo group using a two-sided

Manufacturing

to

between

of 60 mL water, 5 g sorbitol

was added

below the 20-30

maceutical

and the

on a daily basis.

clinical

using

the cyclosporine

Chemical

CA). The sorbitol

the hydrophobic effect.

of 1 hour or overnight

The time that the enema was administered of enema

Gardena,

medi-

just before use, shake vigorously,

the enema for a minimum

if possible. duration

for 4 weeks.

characteristics,

improvement

with regard

models were used to assess the relationship treatment

of one enema nightly

were compared

of Fisher’s Exact Test for ordered categories. the disease

Cyclosporine Enema Treatment

groups

There were no significant cyclosporine

and placebo

comparisons

of demographic

severity (Table 3), initial and current or previous

groups

differences

between

the

with regard to baseline

characteristics

and disease

disease assessment (Figure l), drug therapy (Table 4). The

duration of symptoms can be classified as follows for the cyclosporineand placebo-treated patients, respectively: recent flare (< 30 days), 0 of 20 and 1 of 20; intermediate duration (30-90 days), 5 of 20 and 4 of 20; and chronically active (>90 days), 15 of 20 and 15 of 20. The median

duration

of symptoms

in the cyclosporine

and

placebo groups was 210 and 225 days, respectively (Table 3). Only six patients (two receiving cyclosporine and four receiving placebo) were not receiving concomitant oral corticosteroids and/or salicylates during the study; of these, four had topical corticosteroids or mesalamine therapy withdrawn 2 weeks before the study. Thus, the majority of patients in both groups had chronically active and refractory disease as evidenced by a long duration of

1432 SANDBORN ET AL.

Table 3. Patient

Demographic

40 Patients Treated

GASTROENTEROLOGY Vol. 106, No. 6

Data and Disease

With Left-Sided

Ulcerative

With Cyclosporine

43

Age at entry (yf) Duration of ulcerative colitis (yr) Duration of current symptoms (days) Extent of disease (cm) Initial DAI score (range, O-12) Initial HDAI score (range, O-4)

Median

Range

38

l-4

26-68 o-21

5 210 43

5-11

3 IO/IO

Sex (M/F)

Range

14-6570 lo-60

8

42-3650 12-60

8

4-10

3 13/7

l-4

NOTE. No significant differences were detected for any of these characteristics (P > 0.05). DAI. clinical disease activity index; HDAI, histological disease activity index.

symptoms

and the need

with corticosteroids The

for concomitant

and/or

rates of clinical

oral therapy

salicylates.

and

histological

improvement

after 4 weeks of therapy were not significantly between the placebo and cyclosporine groups patients

with left-sided

ema treatment the 4-week

ulcerative

was discontinued

treatment

period

and Previous

With Left-Sided

Drug Therapy

Ulcerative

colitis

in 40 Patients

Treated

With

Current drug therapy No current treatment Salicylatesa Steroids Salicylates” and steroids Recently discontinued drug therapyb Topical steroids Topical mesalamine Previous drug therapyC Oral steroids Topical steroids Sulfasalazine Olsalazine Oral mesalamine Topical mesalamine Azathioprine or 6mercaptopurine

Placebo (n = 20) (%)

Cyclosporine (n = 20) (%)

20 40 15 25

10 40 20 30

30 15

25 20

30 45 55 10 10 40

20 65 50 I.5 10 60

5

15

NOTE. No significant differences were detected acteristics (P > 0.05). “Salicylates are sulfasalazine, olsalazine, and Therapy discontinued ~~14 days before study Therapy discontinued >I4 days before study

for any of these charoral mesalamine. entry. entry.

different in these

(Table

5). En-

in nine patients

before

was completed

Colitis

Enemas

Cyclosporine (n = 20)

O-24

225 38

Table 4. Current

Cyclosporine

21-69

2

in

Enemas

Placebo (n = 20) Median

Severity Colitis

because

of

worsening symptoms requiring initiation or increase of the dose of corticosteroids and/or hospitalization. This

included

6 of 20 patients

(30%) in the cyclosporine

and 3 of 20 (15 %) in the placebo group. No association between improvement in clinical

dis-

ease activity and colonic tissue cyclosporine concentrations was detected (P > 0.15). Among patients in the cyclosporine group, there was not a significant in the colonic tissue cyclosporine concentrations with clinical

8

group

remission

and improvement

difference for those

(median,

772

ngig; range, O-5885 “g/g) and those who failed to improve (median, 0 rig/g;; range, O-5998 “gig). Similarly,

Table 5. Response

to Treatment

in 40 Patients

0

SCOW

1

2

3

Score

Figure 1. Frequency distribution of baseline scores (O-3 points) for the individual components of the disease activity index: (A) stool frequency, (6) rectal bleeding, (C) sigmoidoscopic findings, and (D) physician global assessment. There were no significant differences in the frequency distribution of scores between the placebo and cyclosporine groups for any of the categories. ?T, ?cyclosporine (n = 20).

Disease activity index Clinical remission Clinical improvement’ Clinical failure Histological disease activity index Histological remission Histological improvement’ Histological failure

With Cyclosporine

With Left-Sided

Ulcerative

Enemas Colitis

Placebo

Cyclosporine

Pa

(n = 20) 1 9 11

(n = 20) 1 8 12

0.90 0.90 0.90

(n = 18) 1 7 11

(n = 19) 1 6 13

0.77 0.77 0.77

a/=’ based on an extension of Fisher’s Exact Test for ordered categories. bClinical improvement includes clinical remission. ‘Histological improvement includes histological remission.

CYCLOSPORINE ENEMAS FOR ULCERATIVE COLITIS

June 1994

enema

retention

time

was not significantly

associated

with improvement in the disease activity index. The median enema retention time in the placebo group was 6.3 hours (range, 2.4-8.3 group ever,

hours), whereas in the cyclosporine

it was 4.1 hours (range, there

retention

1.0-12.7

was significantly

times

greater

for the cyclosporine

Two patients

receiving

verse events during

hours).

variation group

cyclosporine

Howin (log)

(P < 0.01).

experienced

ad-

the study; both received cyclosporine.

One patient had an absolute neutrophil count of 5001 mm3 after 4 weeks in the study. The patient had started taking

sulfasalazine

8 weeks before entering

Both the cyclosporine withdrawn,

enemas

the study.

and the sulfasalazine

and the neutropenia

was later rechallenged

with

absence of sulfasalazine

therapy,

resolved.

cyclosporine

were

The patient enemas

and the neutropenia

in the did

and three patients

twice daily for 4 weeks (2.5 mg/kg 0.75 mg/kg Winter

administering the cyclosporine enemas, the patient developed severe abdominal cramping and worsening diar-

et al. used cyclosporine

cyclosporine

enemas

The present trolled

(350 mg/day

randomized,

tive colitis

was designed

uncontrolled

studies

no significant

differences

between

the

of clinical

and those who were removed

breath test performed

withafter

enema administration to assess for carbohydrate intolerance to the sorbitol in the enema vehicle was negative. Except

for the

patient

with

neutropenia

described

above, none of the patients in the study had any clinically important changes in the following parameters: systolic and diastolic blood pressure, complete blood count, serum chemistry group levels (including alkaline phosphatase, aspartate aminotransferase, total bilirubin, direct bilirubin, creatinine, and urea), and urinalysis. Trough whole blood cyclosporine

concentrations

able in all but two patients receiving receiving

(56 ng/mL

were significantly

of patients

Discussion Four uncontrolled trials have reported improvement of left-sided ulcerative colitis during treatment with cyclosporine enemas. 22,24-26 Brynskov et al. used cyclosporine enemas (250 mg/day for 2 weeks) in seven patients with refractory ulcerative proctitis and one patient with an ileostomy and colitis in the blind rectal stump and reported a response of 75%.** Ranzi et al. treated three patients with refractory proctosigmoiditis

the results

extent

and

of the

improve-

placebo-treated

was actually greater in

(30%) than the placebowere no significant who completed early with

differ-

the study

regard

to the

of disease (43 cm vs. 45 cm for

colitis involving

ing colon did not result in the selection more severe disease. The rate of histological

the descend-

of patients

with

improvement

was even lower than the rate of clinical improvement, and there was not a significant difference between the two groups.

ported

is 25 ng/mL.

There

those patients

with ulcerative

in one patient

peutic level range of 100-300 ng/mL, and the value of 30 ng/mL was near the lower limit of sensitivity for our assay, which

proximal

The negative what surprising.

below the thera-

(15%).

ulcera-

the cyclosporine group and 38 cm vs. 60 cm for the placebo group). These findings suggest that the inclusion

were undetect-

cyclosporine and 30 ng/mL in another patient placebo). The blood cyclosporine concentra-

tions in these patients

median

group

placebo-con-

from the study because

symptoms group

with with

above.2’,24-26 We found

cyclosporine-

symptoms

A hydrogen

we have

in the rate of clinical

the cyclosporine-treated

for

colitis

for left-sided

to confirm

discussed

The rate of early removal

of worsening treated

ulcerative

for 4 weeks).‘*

enemas

ences between

when the enema vehicle was administered

(250 mg/day

double-blind,

trial of cyclosporine

and

of 50%.

reported a 50% response in 10 patients ulcerative colitis after treatment

rhea that lasted for 12 hours. The symptoms recurred with two rechallenges. The patient also experienced similar out cyclosporine.

enemas

rate of 58%.26 Finally,

a response

enemas

in three patients

and reported previously left-sided

ment

after

ileosmucous

with a response

with left-sided

groups.

30 minutes

in three patients)

6 weeks) in 12 patients

to the enema

Approximately

colectomy,

tomy, and colitis in a sigmoidorectal remnant fistula.*’ These patients received cyclosporine

not recur. The other adverse event seemed to be related vehicle.

with prior subtotal

1433

results of our controlled trial are someMultiple uncontrolled studies have re-

improvement

of ulcerative

colitis after treatment

with oral or intravenous cyclosporine2-” with an average response rate of 80%.20 These uncontrolled results were recently confirmed by a controlled trial of intravenous cyclosporine for severe ulcerative colitis, which reported a response of 820/o.‘” In comparison with the apparent efficacy of oral and intravenous cyclosporine for ulcerative colitis, cyclosporine enemas are not efficacious. These findings stand in contrast with other medications used to treat ulcerative colitis, such as corticosteroids and mesalamine, which are efficacious with both oral and topical administration. There are a number of potential explanations for our negative results. First, the dose of cyclosporine may have been too low or the dosing interval too infrequent. The mean oral cyclosporine dose reported to be efficacious in ulcerative colitis is 8 mg kg-’ .day-‘.I0 The cyclosporine

GASTROENTEROLOGY Vol. 106, No. 6

1434 SANDBORN ET AL.

dose

used

in

this

study

was

350

mglday

(5

mg.kg-’ .day-’ for a i’O-kg patient). However, this dose is higher than the doses used in most of the other uncontrolled trials.24-26 Second, the water-based enema vehicle that we and others used’1-26 may not provide optimal delivery of cyclosporine the treatment duration possibility

to the colonic

seems unlikely

ally reported

mucosa.

Third,

may have been too short. because cyclosporine

to act within

l-2

This

is gener-

weeks in patients

with

ulcerative colitis.*’ Fourth, the patients we selected for the study were in general refractory to standard therapy. who have not already

Patients

and salicylate cyclosporine proven

therapy

failed oral corticosteroid

may have a better

enemas than patients

to be refractory

to other medications.

tients with disease in the descending differently sigmoid

than

patients

with

colon and rectum,

disease

by cyclosporine

helper cell interleukin 2 production to stop the inflammatory reaction reported

tween colonic tissue cyclosporine tention

and a strong

time and clinical

Fifth,

pa-

confined

to the

in which case the combining

local immunosuppression

cal response

to

colon may respond

of these two groups could mask treatment

We have previously

response

who have already been

effects. Finally, of colonic

T-

may not be sufficient in ulcerative colitis. a weak association

concentration

association

between

be-

and clinienema re-

response.22 These uncontrolled

observations were not confirmed in the present controlled trial. Whether colonic tissue cyclosporine concentrations are associated

with clinical

response

in patients

treated

with oral or intravenous cyclosporine is unknown, although a preliminary report has suggested that this may be the case.‘> No toxicity clinically

directly

important

attributable

to cyclosporine

side effects were noted

during

or the

trial. Presumably, the absence of toxicity and side effects relates to the fact that the cyclosporine administered as an enema is generally not absorbed. A similar lack of toxicity during cyclosporine enema treatment has been previously reported.2’-26 In contrast, side effects occur frequently when cyclosporine is administered orally or intravenously.20 We conclude that cyclosporine enemas administered in a dose of 350 mglday for 4 weeks are not efficacious in the treatment of mildly to moderately active left-sided ulcerative colitis. Cyclosporine enemas are safe and welltolerated when administered daily for 4 weeks. Future studies should evaluate higher dosages of cyclosporine, more frequent dosing schedules, alternative enema vehicles, patients with disease extent limited to the sigmoid colon (535 cm), and patients who have not already proven refractory to other forms of therapy.

References 1. Hess AD, Tutschka PJ, Santos GW. Effect of cyclosporin A on human lymphocyte response in vitro. III. CsA inhibits the production of T lymphocyte growth factors in secondary mixed lymphocyte responses but does not inhibit the response of primed lymphocytes to TCGF. J lmmunol 1982; 128:355-359. 2. Gupta S, Keshavarzian A, Hodgson HJF. Cyclosporin in ulcerative colitis. Lancet 1984;1:1277-1278. 3. Kirschner BS, Whitington PF, Black DD, Bostwick D. Cyclosporininduced remission in severe colitis unresponsive to corticosteroid therapy (abstr). Pediatr Res 1987;21:271A. 4. Bianchi Porro G, Panza E, Petrillo M. Cyclosporin A in acute ulcerative colitis. ltal J Gastroenterol 1987; 19:40-41. 5. Shelly ED, Shelly WB. Cyclosporine therapy for pyoderma gangrenosum associated with sclerosing cholangitis and ulcerative colitis. J Am Acad Dermatol 1988; 18:1084-1088. 6. Hyams JS, Treem WR. Cyclosporine treatment of fulminant colitis. J Pediatr Gastroenterol Nutr 1989; 9:383-387. 7. Stange EF, Fleig WE, Rehklau E, Ditschuneit H. Cyclosporin A treatment in inflammatory bowel disease. Dig Dis Sci 1989; 34: 1387-1392. 8. Baker K, Jewel1 DP. Cyclosporin for the treatment of severe inflammatory bowel disease. Aliment Pharmacol Ther 1989;3: 143-149. 9. Lichtiger S, Present DH. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis. Lancet 1990;336:1619. 10. Lichtiger S. Cyclosporine therapy in inflammatory bowel disease: open-label experience. Mt Sinai J Med 1990;57:315-319. 11. Bianchi Porro G, Petrillo M, Ardizzone S. Cyclosporin treatment for severe active ulcerative colitis (letter). Lancet 1990;336:439. 12. Gavaler JS, Delemos B, Belle SH, Heyl AE, Tarter RE, Starzl TE, Gavaler C, Van Thiel D. Ulcerative colitis disease activity as subjectively assessed by patient-completed questionnaires following orthotopic liver transplantation for sclerosing cholangitis. Dig Dis Sci 1991;36:321-328. 13. Shaked A, Colonna JO, Goldstein L, Busuttil RW. The interrelation between sclerosing cholangitis and ulcerative colitis in patients undergoing liver transplantation. Ann Surg 1992;215:598-603. 14. Treem WR, Davis PM, Hyams JS. Cyclosporine treatment of severe ulcerative colitis in children. J Pediatr 1991;119:994-997. 15. Sandborn WJ, Goldman DH, Lawson GM, Perrault J. Measurement of colonic tissue cyclosporine concentration in children with severe ulcerative colitis. J Pediatr Gastroenterol Nutr 1992; 15: 125-129. 16. Actis GC, Ottobrelli A, Pera A, Barletti C, Ponti V, Pinna-Pintor M, Verme G. Continuously infused cyclosporine at low dose is sufficient to avoid emergency colectomy in acute attacks of ulcerative colitis without the need for highdose steroids. J Clin Gastroenterol 1993; 17:10-13. 17. Lichtiger S, Present DH. Cyclosporin A in the treatment of severe ulcerative colitis (abstr). Gastroenterology 1992; 102:A653. 18. Sandborn WJ, Wiesner RH, Tremaine WJ, LaRusso NF. Ulcerative colitis disease activity following treatment of associated primary sclerosing cholangitis with cyclosporin. Gut 1993;34:242-246. 19. Lichtiger S, Present DH, Kornbluth A, Hanauer S. Cyclosporin A in the treatment of severe, refractory ulcerative colitis: a double blinded placebo controlled trial (abstr). Gastroenterology 1993; 104:A732. 20. Sandborn WJ, Tremaine WJ. Cyclosporine treatment of inflammatory bowel disease. Mayo Clin Proc 1992;67:981-990. 21. Sandborn WJ, Strong RM, Forland SC, Chase RE, Cutler RE. The pharmacokinetics and colonic tissue concentrations of cyclosporine after IV, oral, and enema administration. J Clin Pharmacol 1991; 31:76-80.

CYCLOSPORINE ENEMAS FOR ULCERATIVE COLITIS

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22. Sandborn WJ, Tremaine WJ, Schroeder KW, Steiner BL, Batts KP, Lawson GM. Cyclosporine enemas for treatment of treatmentresistant, mildly to moderately active, left-sided ulcerative colitis. Am J Gastroenterol 1993;88:640-645. 23. Sandborn WJ, Tremaine WJ. Cyclosporin enemas for therapy-resistant ulcerative proctitis. In: Demling L, Fruhmorgen P, eds. Non-neoplastic diseases of the anorectum. Lancaster, UK: Klewer, 1992:333-339. 24. Brynskov J, Freund L, Thomsen 00, Anderson CB, Rasmussen SN, Binder V. Treatment of refractory ulcerative colitis with cyclosporine enemas. Lancet 1989; 1:721-722. 25. Ranzi T, Campanini MC, Velio P, Quart0 di Palo F, Bianchi P. Treatment of chronic proctosigmoiditis with cyclosporin enemas (letter). Lancet 1989;2:97. 26. Winter T, Dalton HR. Merrett MN, Campbell A, Jewel1 DP. Cyclosporin A retention enemas in refractory distal colitis: an open trial (abstr). Gastroenterology 1992; 102:A947. 27. Jarnerot G, LennardJones J, Bianchi-Porro G, Brynskov J, Campieri M, Present DH. Medical treatment of refractory distal ulcerative colitis. Gastroenterol Int 1991;4:93-98. 28. Truelove SC. Treatment of ulcerative colitis with local hydrocortisone hemisuccinate sodium: a report on a controlled therapeutic trial. Br Med J 1958;2:1072-1077. 29. Baron JH, Connell AM, Lennard-Jones JE. Variation between observers in describing mucosal appearances in proctocolitis. Br Med J 1964; 1:89-92. 30. Schroeder KW, Tremaine WJ, llstrup DM. Coated oral 5aminosalicylic acid therapy for mildly to moderately active ulcerative colitis: a randomized study. N Engl J Med 1987;317:1625-1629. 31. Sninsky CA, Cart DH, Shanahan F, Powers BJ, Sessions JT, Pruitt RE, Jacobs WH, Lo SK, Targan SR, Cerda JJ, Gremillion DE, Snape

32.

33.

34.

35. 36.

1435

WJ, Sabel J, Jinch H, Swinehart JM, DeMicco MP. Oral mesalamine (Asacol) for mildly to moderately active ulcerative colitis. Ann Intern Med 1991; 115:350-355. Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, Martin T, Sparr J, Prokipchuk E, Borgen L. 5-aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology 1987; 92: 1894-1898. Biddle WL, Greenberger NJ, Swan JT, McPhee MS. Miner PB. 5aminosalicylic acid enemas: effective agent in maintaining remission in left-sided ulcerative colitis. Gastroenterology 1988;94: 1075-1079. Venkataramanan R, Burckart GJ, Ptachcinski RJ, Blaha R, Logue LW, Bahrson A, Choo-Seng G, Brady JE. Leaching of diethylhexyl phthalate from polyvinyl chloride bags into intravenous cyclosporine solution. Am J Hosp Pharm 1986;43:2800-2802. Moyer TP, Charlson JR, Ebnet LE. Improved chromatography of cyclosporine. Ther Drug Monit 1986;8:466-468. Moyer TP, Johnson P, Faynor SM, et al. Cyclosporine: a review of drug monitoring problems and presentation of a simple, accurate liquid chromatographic procedure that solves these problems. Clin Biochem 1986; 19:83-89.

Received May 21, 1993. Accepted November 30, 1993. Address requests for reprints to: William 1. Sandborn, M.D., Mayo Clinic, 200 First Street S.W., Rochester, Minnesota 55905. Fax: (507) 284-0538. Supported by a grant from Sandoz Pharmaceutical Corporation. Presented at the annual meeting of the American Gastroenterological Association in Boston, Massachusetts, May 17-19, 1993.