Clinical review

Regular review
Management of Crohns disease
David S Rampton
Introduction
Over recent decades the incidence of Crohns disease
has increased in the United Kingdom and it now affects
about 1 in 1500 people. Symptoms start at any age, with
peaks in early and late adulthood. Although the disease
is incurable its adverse effects on health and quality of
life can be substantially reduced by appropriate
treatment. This paper reviews the current management
of adults with common presentations of Crohns disease.
Methods
I searched Medline with the key terms Crohns disease,
drug therapy, dietary therapy, surgery, and therapy.
Pharmacotherapeutic advances were derived from
peer reviewed controlled clinical trials and meta-
analyses published since 1993. Recent data were from
the annual meeting of the American Gastroenterologi-
cal Association. Citations about other aspects of
Crohns disease were mainly from review articles.
Aetiopathogenesis
The progressive elucidation of the pathogenesis, if not
yet the cause, of Crohns disease has improved our
understanding of the possible modes of action of con-
ventional treatment and has led to the development of
new anti-inflammatory agents aimed at specific patho-
physiological targets.
Epidemiological and genetic studies suggest that
Crohns disease is a polygenic disorder without any
single Mendelian pattern of inheritance. Susceptibility
loci for the disease have been reported recently on
chromosomes 16, 3, 7, and 12; the latter three being
shared with ulcerative colitis.
1
Several environmental
factors have been implicated.
1
Claims for initiating
roles for gut flora, food constituents, or specific
infections such as mycobacterium paratuberculosis
and measles have not yet been substantiated. The
pathogenic significance of the strong association
between cigarette smoking and Crohns disease, and
why smoking worsens the clinical course of the
disease,
2
remains unclear.
Whatever the initiating factors in Crohns disease,
excessive activation of mucosal T cells leads to
transmural inflammation, which is amplified and
perpetuated by the release of proinflammatory
cytokines and soluble mediators (fig 1).
1
Assessment
Treatment of Crohns disease depends not only on the
site of the disease but also on the pathological process
underlying the patients presentation.
3 4
Inflammation,
obstruction, abscess, and fistula need to be dis-
tinguished by appropriate investigation (table). Clinical
evaluation and blood tests
5
remain central to the
assessment of symptomatic Crohns disease, but
recently there have been changes in the subsequent
diagnostic approach.
Conventional radiology and colonoscopy
Plain abdominal radiography is still essential if intesti-
nal obstruction is suspected: as in ulcerative colitis it
helps to estimate the extent and severity of Crohns
colitis. For imaging the small intestine a barium follow
through is more comfortable for patients, is less likely
to miss proximal disease, and is safer than a small
bowel enema (enteroclysis).
6
Colonoscopy with ileos-
copy, because it allows detection of superficial disease,
biopsy and, when necessary, dilatation of strictures is
Summary points
Morbidity from Crohns disease can be lessened
by meticulous specialist management
New techniques for clarifying the site of disease,
activity, and complications include scanning with
radiolabelled leucocytes, ultrasound, computed
tomography, and magnetic resonance imaging
Budesonide, high dose mesalazine and, for
refractory disease, methotrexate and antitumour
necrosis factor antibody are new therapeutic
options
Other new therapeutic possibilities include a
liquid formula diet, endoscopic stricture
dilatation, and laparoscopic surgery
The most effective measure for maintenance of
remission is stopping smoking
Patients should participate in decisions about
their treatment
Gastrointestinal
Science Research
Unit and Digestive
Diseases Research
Centre,
St Bartholomews
and the Royal
London School of
Medicine and
Dentistry, London
E1 2AD
David S Rampton
reader in
gastroenterology
Correspondence to:
Department of
Gastroenterology,
Royal London
Hospital, London
E1 1BB
drampton@mds.
qmw.ac.uk
BMJ 1999;319:14805
1480 BMJ VOLUME 319 4 DECEMBER 1999 www. bmj.com
now usually preferred to barium enema for investiga-
tion of the lower bowel (fig 2).
6
Colonoscopy may also
have a role, as in ulcerative colitis, in surveillance for
colorectal cancer in patients with longstanding
extensive Crohns colitis.
7
Newer imaging techniques
Scanning with radiolabelled leucocytes identifies sites
of intestinal inflammation and intra-abdominal abscess
non-invasively. Labelling with
99
technetium-
hexamethyl propylene amine oxime is superior to
111
indium tropolonate in ease of use, availability, image
quality, and radiation dose.
6
Scintigraphic scanning
with monoclonal antibodies to upregulated cellular
adhesion molecules such as E selectin represents an
ingenious application of improved understanding of
the pathogenesis of Crohns disease.
1 8
Transabdominal ultrasound for the assessment of
bowel wall abnormalities, abscess, and fistula is
becoming more widespread.
6
Changes in mucosal and
superior mesenteric arterial blood flow indicating
active Crohns disease are detectable by colour
Doppler ultrasound, whereas endoanal and transvagi-
nal ultrasound can help to evaluate perianal disease.
Although its non-invasive nature and lack of radiation
exposure make ultrasound an appealing investigative
technique results are dependent on operator skill and
equipment quality.
Abdominal computed tomography now has a
major role in the diagnosis of abscess, fistula, and peri-
anal and parastomal complications of Crohns disease.
6
The contribution of magnetic resonance imaging is
evolving but it is already invaluable for the delineation
of pelvic and perianal disease.
9
Treatment of active ileocaecal Crohns
disease
General measures
Explanation, hospital care, and dietary advice
Patients need their illness fully explained, not least to
enable them to participate in decisions about their
therapy: discussion can be reinforced with information
from support groups such as the National Association
for Colitis and Crohns disease. Hospital care is best
undertaken by a team of medical and surgical
gastroenterologists, dieticians, and nurse practitioners
with a special interest in inflammatory bowel disease,
nutrition, and stoma care. Undernourished patients
need liquid protein supplements, whereas special
nutritional measures are required for patients with
short bowel syndrome due to extensive Crohns disease
or resection.
10
Non-specific drugs
Codeine phosphate and loperamide remain useful
antidiarrhoeal agents in Crohns disease but may cause
acute colonic dilatation in active colitis. By binding bile
salts cholestyramine (4 g 1-3 times daily) reduces diar-
rhoea due to terminal ileal disease or resection.
Haematinics, calcium, magnesium, zinc, and fat soluble
vitamins may be needed for the replacement of
particular deficiencies as may bisphosphonates, cal-
cium, vitamin D, and hormone replacement therapy
for osteoporosis. Sick inpatients may require intra-
T-cell activation
Granulomatous vasculitis
Mucosal damage
Mucosa
Epithelium
Cytokine release
Tumour necrosis factor
Interferon
Interleukins 1, 2, 6, and 12 Endothelial cell activation
Recruitment and activation of
neutrophils and monocytes
Soluble mediators
elcosanoids, reactive oxygen
metabolites, nitric oxide,
proteases
Genetic predisposition
Environmental factors
Food constituents, gut flora,
specific infections, smoking
Increased permeability
Fig 1 Aetiopathogenesis of Crohns disease. Genetic and environmental factors activate
mucosal T lymphocytes causing cytokine driven inflammation; increased epithelial
permeability and granulomatous vasculitis, leading to focal intestinal microinfarction, may
also contribute to the inflammatory process
1
Usefulness of imaging techniques for assessment of Crohns disease
Information obtained
Site Activity Complications*
Conventional radiology:
Plain abdominal film + +
Barium follow through ++ ++ +
Ileocolonoscopy and biopsy ++ ++ +
Newer imaging techniques:
Radiolabelled leucocyte scan + ++ +
Ultrasound + +
Computed tomography + ++
Magnetic resonance imaging ++
*Abscess, fistula, perianal disease.
Fig 2 Superficial aphthoid erosions in sigmoid colon in patient with
ileocolonic Crohns disease. Subtle lesions such as these are more
readily seen at ileocolonoscopy than on barium enema
Clinical review
1481 BMJ VOLUME 319 4 DECEMBER 1999 www. bmj.com
venous fluid and electrolytes and blood transfusion,
with subcutaneous heparin to reduce the risk of
systemic venous thromboembolism.
11
Non-steroidal
anti-inflammatory drugs may precipitate relapse of
inflammatory bowel disease
12
and should be avoided.
Specific drug therapy
Clinical trials in Crohns disease are bedevilled by diffi-
culties in defining outcome measures, and by the
heterogeneity, fluctuating course, and unpredictable
placebo response of the disease.
13
Nevertheless, several
new treatments have been introduced recently as a
result of well conducted controlled trials.
Corticosteroids
In active disease oral steroids still provide the quickest
and most reliable response; about 70% of patients
improve within 4 weeks. Conventionally, prednisolone
(40-60 mg/day) is used, the dose being tapered by 5
mg every 7-10 days once improvement has begun.
Very ill patients, or those with intestinal obstruction,
need intravenous hydrocortisone or methylpred-
nisolone initially.
Budesonide is a new steroid with high topical
potency; because of poor absorption and rapid first
pass metabolism it causes less adrenocortical suppres-
sion than prednisolone. Formulated in a pH sensitive
coating, which delivers the drug to the distal ileum and
caecum, budesonide (Entocort CR (Astra) or Budeno-
falk (Cortecs), 9 mg/day) approaches oral pred-
nisolone (40 mg/day) in efficacy in ileocaecal Crohns
disease.
1416
It has become a useful although compara-
tively expensive option for patients in whom minimisa-
tion of steroid induced side effects is particularly
important.
Aminosalicylates
The newer oral 5-aminosalicylate formulations are
better tolerated than sulphasalazine and can be used in
higher doses. The pH dependent delayed release
(Asacol, Salofalk) and, particularly, slow release
(Pentasa) mesalazine preparations release
5-aminosalicylate more proximally in the gut than sul-
phasalazine making them useful in small bowel disease
as well as colitis. High dose oral mesalazine (Pentasa
2 g twice daily, Asacol 1.2 g three times daily) given for
up to 4 months induces remission in about 40% of
patients with moderately active ileocaecal Crohns
disease.
1618
However, even mesalazine may cause rash,
headache, nausea, diarrhoea, pancreatitis, or blood
dyscrasias in up to 5% of patients; interstitial nephritis
occurs in around 1 in 500.
19
Antibiotics
Metronidazole alone
3 4
or with ciprofloxacin
20
is
moderately effective in active Crohns disease.
Treatment is given for up to 3 months but may be
complicated by nausea, an unpleasant taste, alcohol
intolerance, and a peripheral neuropathy, which can
be irreversible. Preliminary reports have suggested
possible therapeutic roles for ciprofloxacin, clarithro-
mycin, rifabutin, and clofazimine, singly or in
combination,
3 4
but conventional antituberculous
triple therapy is ineffective.
21
Immunosuppressive drugs
For patients refractory to, or dependent on, cortico-
steroids, who because of extensive disease or previous
resection need to avoid surgery, adjunctive azathio-
prine (2-2.5 mg/kg/day) or 6-mercaptopurine (1-1.5
mg/kg/day) remain invaluable, the dose of steroids
being tapered as improvement occurs.
22
Response to
the thiopurines may take up to 4 months, but hopes
that intravenous azathioprine could be used to acceler-
ate improvement have not been confirmed by a
controlled trial.
23
Homozygous deficiency of
6-thiopurine methyltransferase, the enzyme responsi-
ble for the safe metabolic disposal of purine analogues,
occurs in about 0.2% of people and may predispose to
azathioprines occasionally serious side effects (bone
marrow depression,
24
acute pancreatitis, chronic hepa-
titis). Routine assay of 6-thiopurine methyltransferase
is not yet available but in the future may help identify
patients at particular risk. The British National
Formulary recommends that patients starting a thiopu-
rine require blood counts every week for the first 8
weeks of treatment and at least every 3 months there-
after. Existing data about the risk of malignancy in
patients with Crohns disease given thiopurines long
term are reassuring.
25
It is not yet clear how long
azathioprine or 6-mercaptopurine should be used in
Crohns disease. However, in patients maintained in
remission on a thiopurine the risk of relapse after 4
years seems to be similar whether the drug is
continued or stopped.
26
Methotrexate 25 mg intramuscularly weekly
improves symptoms and reduces steroid requirements
in about 40% of patients with chronically active steroid
dependent Crohns disease,
27
but its side effects (bone
marrow depression, hepatic fibrosis, pneumonitis,
opportunistic infections) restrict its use to patients with
very refractory disease. A lower oral dose (12.5 mg
weekly) may also have a beneficial effect and prove
safer.
28
Patients given methotrexate need blood
monitoring as for azathioprine and 6-mercaptopurine;
the necessity for routine lung function tests, chest x ray,
or liver biopsy is not clear.
Cyclosporin has not been confirmed as useful in
ileocaecal Crohns disease.
3
However, data from an
unblinded controlled trial show that mycophenolate
mofetil, an immunosuppressive drug that inhibits
purine synthesis in lymphocytes, produces a quicker
response than azathioprine in patients taking steroids
with active Crohns disease, with few adverse effects
29
:
this report requires confirmation in a double blind
controlled study.
Antitumour necrosis factor antibody
The first specific cytokine related therapy to reach
clinical application in Crohns disease is infliximab, a
mouse-human chimeric antibody (cA2) to tumour
necrosis factor ; this preparation was launched in the
United States in late 1998 and in the United Kingdom
in September 1999.
30 31
In patients with Crohns disease refractory to
steroids or conventional immunosuppressive drugs a
single infusion of infliximab at 4 weeks produced
improvement in 64% of patients and remission in 33%
compared with 17% and 4% respectively after
placebo.
30
Relapse tended to occur in the ensuing
Clinical review
1482 BMJ VOLUME 319 4 DECEMBER 1999 www. bmj.com
months: repeated infusions at 4-8 weeks may produce
more lasting remissions.
32
Infliximab is infused intravenously over 2 hours
each 5 mg/kg infusion costs about 1000. Infusion
reactions occur in up to 20% of patients and mean
that treatment should be given in hospital, albeit on a
daycare basis, where full resuscitation facilities are
available. Common minor side effects include
headache, nausea, and upper respiratory tract
infections. Serious, although not opportunistic, infec-
tions including salmonella enterocolitis, pneumonia,
and cellulitis have been reported. The production of
human antichimeric antibodies may cause delayed
hypersensitivity reactions (arthralgia, fever, rash) in
patients given a repeat infusion after an interval of
2 or more years; anti-double stranded DNA and
cardiolipin antibodies may cause a lupus syndrome.
Rapid healing and fibrosis of intestinal strictures may
precipitate obstruction. Lastly, there are reports of
lymphoma in patients given infliximab for Crohns
disease and rheumatoid arthritis, although it is not yet
clear if these are a complication of the disease or due
to the drug.
In the future, selection of patients to be treated with
antitumour necrosis factor antibody may depend on
their genotype as well as disease phenotype: patients
with particular tumour necrosis factor microsatellite
haplotypes, for instance, may respond poorly to inflixi-
mab.
33
At present, because of uncertainties about its
efficacy, safety and, cost-benefit ratio antitumour
necrosis factor antibody should be restricted to
patients with very refractory inflammatory disease.
Possible new treatments
The place of other new approaches specifically target-
ing steps in the inflammatory process awaits clarifica-
tion. Possible treatments include bone marrow
transplant, lymphapheresis, antiCD4 and cellular
adhesion molecule antibodies, interleukin 10, inter-
leukin 11, and antisense oligonucleotides to nuclear
transcription factors.
3437
Dietary therapy
In patients with a poor response to, or preference for
avoiding, corticosteroids, and particularly in children, a
liquid formula diet is a valuable option. Elemental
(amino acid based), oligomeric (containing peptides),
and polymeric (containing whole protein) feeds all
approach the efficacy of corticosteroids if taken for 4-6
weeks as the sole nutritional source.
38
The usefulness of
enteral therapy is unfortunately limited by its cost, the
difficulty many patients have in adhering to it, the need
often to give the feed by nasogastric tube or
percutaneous gastrostomy, and the high relapse rate
that follows its discontinuation.
10 38
Surgery
Surgery is usually indicated for patients whose
ileocaecal disease fails to respond to drug or dietary
therapy. Resection is not curative: there is a 50%
chance of recurrence requiring further surgery at 10
years. Some patients prefer surgery at presentation to
pharmacological or nutritional treatment of indefinite
duration, but there are no controlled data to confirm
the best approach. Although right hemicolectomy
and stricturoplasty can both now be undertaken
laparoscopically trials are required to compare open
and laparoscopic surgery in this setting.
39
Treatment of other common
presentations of active Crohns disease
Obstructive small bowel disease
A raised platelet count, erythrocyte sedimentation rate,
or C reactive protein concentration,
5
and a positive
radiolabelled leucocyte scan may distinguish active
from fibrostenotic Crohns disease, but usually a trial of
intravenous corticosteroids is given. Parenteral nutri-
tion is required if resumption of eating is unlikely
within a week. Although patients not settling after
48-72 hours of conservative treatment usually need
surgery, short upper jejunal, terminal ileal, or colonic
strictures can now be treated by enteroscopic or
colonoscopic balloon dilatation
40
; the value of con-
comitant intralesional injection of triamcinolone is
uncertain.
41
Intra-abdominal abscess
Ultrasound and computed tomography are now used
not only diagnostically but also to drain abscesses per-
cutaneously. In patients whose abscesses have no
enteric connection, this approach can obviate surgery.
6
Intestinal fistula
Where there is no obstruction distal to the site of the
fistula, enteral or parenteral nutrition, an oral
thiopurine, or intravenous cyclosporin or antitumour
necrosis factor antibody cause some fistulae to
heal.
3 22 31
Many patients, however, still require surgical
resection of the fistula and involved intestine.
Perianal disease
Non-suppurative perianal Crohns disease may
respond to oral metronidazole or ciprofloxacin, or
Principles of treatment of active ileocaecal
disease
General measures
Explanation, multidisciplinary care
Nutritional support
Drugsantidiarrhoeals, haematinics, heparin
(inpatients); avoid non-steroidal anti-inflammatory
drugs
Specific pharmacological options
Intravenous corticosteroids then tapered oral
prednisolone or budesonide
High dose mesalazine
Metronidazole alone or with ciprofloxacin
Azathioprine or 6-mercaptopurine (steroid
non-responders)
Methotrexate (thiopurine and steroid non-responders)
Antitumour necrosis factor antibody (thiopurine and
steroid non-responders)
Nutritional therapy
Liquid formula diet
Endoscopic treatment
Balloon dilatation of strictures
Surgery
Resection or stricturoplasty
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1483 BMJ VOLUME 319 4 DECEMBER 1999 www. bmj.com
both, given for up to 3 months
3 4
and to long term
thiopurine.
22
Successful healing of perianal fistulae was
reported in 62% of patients treated with three
intravenous infusions over 6 weeks of antitumour
necrosis factor antibody compared with 26% of those
given placebo.
31
Although reopening of fistulae was
common in the 3 months after treatment was stopped,
antitumour necrosis factor antibody may prove a
useful advance in patients with refractory perianal dis-
ease. Patients with suppurating perianal Crohns
disease need surgery, minimised as far as possible:
abscesses are drained and loose (seton) sutures
inserted to facilitate the continued drainage of chronic
fistulae.
42
Crohns colitis
Medical treatment of active Crohns colitis resembles
that of active ulcerative colitis. Oral or, in ill patients,
intravenous corticosteroids remain the mainstay of
treatment. Colonic release formulations of budesonide
are under development. Oral aminosalicylates, includ-
ing sulphasalazine, are an alternative in patients not
acutely ill.
3 4
In contrast with ulcerative colitis about
50% of patients with moderately active Crohns colitis
respond to oral metronidazole for up to 3 months,
3
but
there are no data about the efficacy of cyclosporin.
Compliant patients with Crohns colitis, like ileitis, may
respond to a liquid formula diet.
38
In patients who require total panproctocolectomy
permanent ileostomy is usually preferred to ileoanal
pouch because of a high incidence of pouch
breakdown and sepsis in Crohns disease. However, a
recent series suggests that ileoanal pouches may be
viable in patients with Crohns disease without perianal
or small bowel disease.
43
Maintenance of remission of Crohns
disease
The most effective prophylactic measure in patients
who smoke is to stop: the risk of relapse in
non-smokers at 5 years is about 30% lower than in
smokers.
2
The efficacy of drug prophylaxis is limited
and depends on whether remission has been achieved
by medical or surgical treatment.
Patients in remission after medical treatment
Meta-analysis shows that, unlike in ulcerative colitis,
long term aminosalicylates have little or no prophylac-
tic effect in this setting.
44
Prednisolone in safe doses has
no routine prophylactic role.
3 4
Unfortunately long
term budesonide (6 mg/day), although less likely to
cause steroid related complications, delays time to
relapse without increasing the remission rate at 1
year.
45 46
Thiopurines are of proved value in maintain-
ing remission and reducing steroid requirements in the
minority of patients dependent on long term
corticosteroids in whom symptoms recur whenever
their dose is reduced.
22
High potency ileal release fish oil capsules
(Purepa), if commercially available, would be an attrac-
tive option should their prophylactic efficacy in one
study
47
be confirmed.
Patients in remission after surgical treatment
Long term aminosalicylates (at least 3 g/day mesala-
zine) reduce the risk of symptomatic relapse after
resection by less than 15%.
44
Oral budesonide (6
mg/day) halves endoscopic, although not sympto-
matic, recurrence rate at 1 year after resection for active
but not fibrostenotic Crohns disease.
48
Oral metroni-
dazole given for 3 months postoperatively reduces
symptomatic as well as endoscopic recurrence rate at 1
year although not over a longer period
49
: it may be a
useful option in patients reluctant to take drugs long
term.
The future
Advances in medical treatment are likely to take
several directions. Efforts are being made to formulate
corticosteroids, aminosalicylates, and azathioprine in
ways that focus delivery more accurately to the site of
the disease. Our improved understanding of the aetio-
pathogenesis of Crohns disease will lead to the devel-
opment of further drugs, of which antitumour
necrosis factor antibody has been the first to reach
the bedside, that are selectively targeted at specific
points in the inflammatory pathway. The choice of
treatment will depend increasingly not only on the
Current management of other common
presentations of Crohns disease
Subacute obstruction
Intravenous corticosteroids, fluids, nasogastric suction
Endoscopic balloon dilatation (if accessible)
Surgery
Intra-abdominal abscess
Antibiotics
Percutaneous drainage
Surgery
Intestinal fistula
Enteral or parenteral nutrition
Azathioprine, 6-mercaptopurine, or intravenous
cyclosporin
Antitumour necrosis factor antibody
Surgery
Perianal disease
Metronidazole or ciprofloxacin, or both
Azathioprine or 6-mercaptopurine
Antitumour necrosis factor antibody
Surgery
Colitis
Corticosteroids
Aminosalicylates
Metronidazole
Liquid formula diet
Surgery
Maintenance of remission in Crohns disease
Remission achieved medically
Stop smoking
Azathioprine or 6-mercaptopurine (patients
dependent on steroids)
Remission achieved surgically
Stop smoking
Mesalazine
Metronidazole (3 months only)
Clinical review
1484 BMJ VOLUME 319 4 DECEMBER 1999 www. bmj.com
phenotypic expression of patients disease but also on
their genotype. Finally, gene therapy, for example,
applied topically to inflamed gut mucosa is an
imminent possibility.
In view of the increasing variety and complexity of
therapeutic options it will be essential to ensure that
the patient remains at the centre of the decision mak-
ing process as the fully informed and final arbiter of
the type of treatment he or she is to be given.
The address of the National Association for Colitis and Crohns
Disease is 4 Beaumont House, Sutton Road, St Albans, Herts
AL1 5HH.
Competing interests: DSR has received grants from Astra,
Ferring, GlaxoWellcome, Janssen-Cilag, Pharmacia-Upjohn,
Roche, SmithKline Beecham, and Wyeth for recruiting patients
to clinical trials (none relevant to this review), for self initiated
pathophysiological studies, for giving non-promotional lectures,
and for travel to international meetings.
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Endpiece
Dangers for surgeons
Surgeons must be very careful
When they take the knife!
Underneath their fine incisions
Stirs the CulpritLife!
Emily Dickinson
Clinical review
1485 BMJ VOLUME 319 4 DECEMBER 1999 www. bmj.com