Bogomolets National Medical University

Department of internal medicine №1

Inflammatory bowel disease

Essay

3rd European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis

2017

3rd European Evidence-based Consensus on Diagnosis and Management of Crohn’s Disease

2016

Davidsons Principles and Practice of medicine 22ed 2014

Kyiv-2017
Diagnosis
Crohn’s disease
Ulcerative colitis
Codes of the disease for ICD-10
K.50. Crohn's disease (regional enteritis)
- K.50.0 Crohn's disease of the small intestine
- K.50.1 Colon cancer disease
- K.50.8 Crohn's disease of the small and large intestine.
- K.50.9 Crohn's disease, unspecified
K.51. Ulcerative colitis
- K.51.0 Ulcerative (chronic) pancolitis
- K.51.2 Ulcerative (chronic) proctitis
- K.51.3 Ulcerative (chronic) rectosigmoiditis
- K.51.4 Inflammatory polyps of large intestine
- K.51.5 Left-sided colitis
- K.51.8 Other ulcerative colitis
- K.51.9 Ulcerative colitis, unspecified

Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic inflammatory bowel diseases
which pursue a protracted relapsing and remitting course, usually extending over years. The
diseases have many similarities and it is sometimes impossible to differentiate between them. A
crucial distinction is that ulcerative colitis only involves the colon, while Crohn’s disease can
involve any part of the gastrointestinal tract from mouth to anus.

Short epidemiological information

According to ECCO, about 2.2 million people in Europe (5 million worldwide) suffer from this
group of diseases. Crohn's disease and ulcerative colitis are the two most common forms of
inflammatory bowel disease. The number of patients with Crohn's disease (CD) in Ukraine is not
known exactly, because the registry has not been created. According to experts, the estimated
number of patients with CD in Ukraine is 13,800 (30.33 per 100,000 people), of whom 6,600
(48%) are patients with moderate to severe activity.
In 2013, 9421 patients with ulcerative colitis (UC) were registered in Ukraine (20.8 per 100 000
people). There is a tendency to an increase in the number of severe, resistant to treatment forms
of chronic inflammatory bowel diseases (IBD), complications and surgical interventions leading
to disability of patients of young, working age. All this, in turn, causes significant economic
costs associated with the care, treatment and rehabilitation of patients.

Pathophysiology
Inflammatory bowel disease has both environmental and genetic components. It is thought that
IBD develops because genetically susceptible individuals mount an abnormal inflammatory
response to environmental triggers, such as intestinal bacteria. This leads to inflammation of the
intestine with release of inflammatory mediators, including TNF, IL-12 and IL-23, which cause
tissue damage. In both diseases, the intestinal wall is infiltrated with acute and chronic
inflammatory cells but there are important differences between the conditions in the distribution
of lesions and in histological features.
Ulcerative colitis
Inflammation invariably involves the rectum (proctitis) and spreads proximally in a continuous
manner to involve the entire colon in some cases (pancolitis). In long-standing pancolitis, the
bowel can become shortened and post-inflammatory ‘pseudopolyps’ develop. The inflammatory
process is limited to the mucosa. Both acute and chronic inflammatory cells infiltrate the lamina
propria and the crypts (‘cryptitis’). Crypt abscesses are typical. Dysplasia, characterised by
heaping of cells within crypts, nuclear atypia and increased mitotic rate, may herald development
of colon cancer.

Crohn’s disease
The sites most commonly involved are, in order of frequency, the terminal ileum and right side
of colon, colon alone, terminal ileum alone, ileum and jejunum. The entire wall of the bowel is
oedematous and thickened, and there are deep ulcers which often appear as linear fissures; thus
the mucosa between them is described as ‘cobblestone’. These may penetrate through the bowel
wall to initiate abscesses or fistulae involving the bowel, bladder, uterus, vagina and skin of the
perineum. The mesenteric lymph nodes are enlarged and the mesentery is thickened. Crohn’s
disease has a patchy distribution and the inflammatory process is interrupted by islands of
normal mucosa.

Clinical manifestations
Ulcerative colitis
The cardinal symptoms are rectal bleeding with passage of mucus and bloody diarrhoea. The
presentation varies, depending on the site and severity of the disease, as well as the presence of
extra-intestinal manifestations.
The first attack is usually the most severe and is followed by relapses and remissions. Emotional
stress, intercurrent infection, gastroenteritis, antibiotics or NSAID therapy may all provoke a
relapse. Proctitis causes rectal bleeding and mucus discharge, accompanied by tenesmus. Some
patients pass frequent, small volume fluid stools, while others pass pellety stools due to
constipation upstream of the inflamed rectum. Constitutional symptoms do not occur. Left-sided
and extensive colitis causes bloody diarrhoea with mucus, often with abdominal cramps. In
severe cases, anorexia, malaise, weight loss and abdominal pain occur, and the patient is toxic,
with fever, tachycardia and signs of peritoneal inflammation.

Crohn’s disease
The major symptoms are abdominal pain, diarrhoea and weight loss. Diarrhoea is usually watery
and does not contain blood or mucus. Almost all patients lose weight because they avoid food,
since eating provokes pain. Weight loss may also be due to malabsorption, and some patients
present with features of fat, protein or vitamin deficiencies.
Crohn’s colitis presents in an identical manner to ulcerative colitis, but rectal sparing and the
presence of perianal disease are features which favour a diagnosis of Crohn’s disease. Many
patients present with symptoms of both small bowel and colonic disease. A few patients present
with isolated perianal disease, vomiting from jejunal strictures or severe oral ulceration.
Physical examination often reveals evidence of weight loss, anaemia with glossitis and angular
stomatitis. There is abdominal tenderness, most marked over the inflamed area. An abdominal
mass may be palpable and is due to matted loops of thickened bowel or an intra-abdominal
abscess. Perianal skin tags, fissures or fistulae are found in at least 50% of patients.
 Complications
 Life-threatening colonic inflammation (toxic megacolon)
 Haemorrhage
 Fistulae
 Cancer
 Extra-intestinal complications (Box 1)
Box 1. Extra-intestinal complications of IBD
Occur during the active phase of Unrelated to inflammatory
inflammatory bowel disease bowel disease activity
o Conjunctivitis o Autoimmune hepatitis
o Iritis o Primary sclerosing cholangitis and
o Episcleritis cholangiocarcinoma (ulcerative colitis)
o Mouth ulcers o Gallstones
o Mesenteric or portal vein thrombosis o Amyloidosis and oxalate calculi
o Fatty liver o Sacroiliitis/ankylosing spondylitis
o Liver abscess/portal pyaemia (Crohn’s with HLA-B27)
o Venous thrombosis o Metabolic bone disease
o Large-joint arthritis
o Erythema nodosum
o Pyoderma gangrenosum

Investigations
Investigations are necessary to confirm the diagnosis, define disease distribution and activity,
and identify complications. A single gold standard for the diagnosis of CD and UC is not
available. The diagnosis is confirmed by clinical evaluation and a combination of endoscopic,
histological, radiological, and/or biochemical investigations.

Initial laboratory investigations

 Full blood count (may show anaemia resulting from bleeding or malabsorption of iron, folic
acid or vitamin B12)
 ESR and CRP
 Faecal calproctectin (has a high sensitivity for detecting gastrointestinal inflammation; is
particularly useful in distinguishing inflammatory bowel disease from irritable bowel syndrome
at diagnosis, and for subsequent monitoring of disease activity)
 Stool microscopy, culture and examination for Clostridium difficile toxin or for ova and cysts.

Investigations for establishing the diagnosis

 Endoscopy
- ileocolonoscopy
- flexible sigmoidoscopy (during acute severe presentations when ileocolonoscopy may confer
an unacceptable risk)
- upper endoscopy (in CD)
- capsule endoscopy and enteroscopy (in CD)
 Histology (two biopsies should be taken from each anatomical segment (terminal ileum, right
colon, transverse colon, left colon and rectum) to confirm the diagnosis and define disease
extent, and also to seek dysplasia in patients with long-standing colitis)
 Radiology
 -CT colonogram
-Barium enema

Investigations for establishing the extent of disease and extramural complications

 MRI/CT; MRI/CT enterography (MRI is preferred)
 Trans-abdominal US
 Plain abdominal X-ray
Is essential in the management of patients who present with severe active disease. Dilatation of
the colon, mucosal oedema (thumb-printing) or evidence of perforation may be found. In small
bowel Crohn’s disease, there may be evidence of intestinal obstruction or displacement of
bowel loops by a mass.

Management
Drugs that are used in the treatment of IBD are listed in Box 2.

Box 2. Drugs used in the treatment of inflammatory bowel disease

Class Mechanism of action Notes
Aminosalicylates Modulate cytokine release from No proven value in CD
(mesalazine mucosa Available as oral or topical (enema/suppository)
(Asacol, Salofalk, Pentasa, Delivered to colon by one of three Sulfasalazine causes side-effects in 10–45%:
Mezavant), olsalazine, mechanisms: headache, nausea, diarrhoea, blood dyscrasias
sulfasalazine, balsalazide) 1. pH-dependent (Asacol, Other aminosalicylates better tolerated;
Salofalk) diarrhoea, headache
2. time-dependent (Pentasa) in 2–5%
3. bacterial breakdown by colonic Rarely, renal impairment
bacteria from a carrier molecule
(sulfasalazine, balsalazide)
Corticosteroids Anti-inflammatory Topical, oral or IV, according to disease
(prednisolone, Budesonide is a potent severity
hydrocortisone, budesonide) corticosteroid Budesonide considered for active ileitis and
efficiently cleared from ileocolitis
circulation by liver, thereby High vigilance for complications
minimising adrenocortical Never used for maintenance therapy
suppression and steroid side- Calcium/vitamin D supplements
effects
Thiopurines (azathioprine, Immunomodulation by inducing Effective after 12 wks of starting therapy
mercaptopurine) T-cell apoptosis Complications leading to drug withdrawal in
Azathioprine is metabolised in ~20%.
liver to mercaptopurine, then by Flu-like syndrome with myalgia, nausea and
thiopurine methyltransferase vomiting
(TPMT) to thioguanine Leucopenia in 3%, particularly in inherited
nucleotides TPMT deficiency (TPMT levels checked prior
to therapy)
Hepatotoxicity; pancreatitis
60% of those intolerant of azathioprine will
tolerate mercaptopurine
Increase in lymphoma (approximately 2–3-fold)
and non-melanoma skin cancer (life-long sun
protection advised)
Metabolite levels can be measured to tailor
therapy
Methotrexate Anti-inflammatory Intolerance in 10–18%. Maximal efficacy when
given by SC injection once weekly. Nausea,
stomatitis, diarrhoea, hepatotoxicity and
pneumonitis. Co-prescription of folic acid and
antiemetics. Teratogenic
Ciclosporin Inhibits T-cell activation Rescue therapy to prevent surgery in UC
 responding poorly to corticosteroids. No value
in CD
Major side-effects in 0–17%: nephrotoxicity,
infections, neurotoxicity (including fits)
Minor complications in up to 50%: tremor,
paraesthesiae, abnormal liver function tests,
hirsutism
Anti-TNF antibodies Suppress inflammation and Moderately to severely active CD, including
(infliximab and induce apoptosis of inflammatory fistulating disease
adalimumab) cells Moderate–severe UC and acute severe UC as
rescue therapy
Acute (anaphylactic) and delayed (serum
sickness) infusion reactions after multiple
infusions
Contraindicated in the presence of infections;
reactivation of latent tuberculosis
Increased risk of infections and possibly of
malignancy
Antibiotics Antibacterial Useful in perianal CD and pouchitis
Major concern is peripheral neuropathy with
long-term metronidazole
Antidiarrhoeal agents Reduce gut motility and small Avoided in acute flare-ups of disease
(loperamide, co- bowel secretion May precipitate colonic dilatation
phenoxylate) Loperamide improves anal
function

The key aims of medical therapy are to:

• treat acute attacks (induce remission)
• prevent relapses (maintain remission)
• prevent bowel damage
• detect dysplasia and prevent carcinoma
• select appropriate patients for surgery.

Ulcerative colitis
Active proctitis
Most patients with ulcerative proctitis respond to a 1 g mesalazine suppository but some will
additionally require oral 5-aminosalicylate (5-ASA) therapy. Topical corticosteroids are less
effective and are reserved for patients who are intolerant of topical mesalazine. Patients with
resistant disease may require treatment with systemic corticosteroids and immunosuppressants.

Active left-sided or extensive ulcerative colitis

In mild to moderately active cases, the combination of a once daily oral and a topical 5-ASA
preparation (‘top and tail approach’) is usually effective. The topical preparation (1 g foam or
liquid enema) is typically withdrawn after 1 month. The oral 5-ASA is continued long-term to
prevent relapse and minimise the risk of dysplasia.
In patients who do not respond to this approach within 2–4 weeks, oral prednisolone (40 mg
daily, tapered by 5 mg/week over an 8-week total course) is indicated.
At the first signs of corticosteroid resistance (lack of efficacy) or in patients who require high
corticosteroid doses to maintain control, immunosuppressive therapy with a thiopurine should be
introduced.
Severe ulcerative colitis
Patients who present with acute severe colitis are best managed in hospital and should be
monitored jointly by a physician and surgeon.
All patients should be given supportive treatment with intravenous fluids to correct dehydration,
and enteral nutritional support should be provided for malnourished patients.
Intravenous corticosteroids (methylprednisolone 60 mg or hydrocortisone 400 mg/day) should be
given by intravenous infusion or bolus injection. Topical and oral aminosalicylates have no role
to play in the acute severe attack. Response to therapy is judged over the first 3 days.
Patients who do not respond promptly to corticosteroids should be considered for medical rescue
therapy with ciclosporin (intravenous infusion or oral) or infliximab (5 mg/kg), which, in
approximately 60% of cases, can avoid the need for urgent colectomy.
Patients who develop colonic dilatation (> 6 cm), those whose clinical and laboratory
measurements deteriorate and those who do not respond after 7–10 days’ maximal medical
treatment usually require urgent colectomy.

Maintenance of remission. Life-long maintenance therapy is recommended for all patients with
left-sided or extensive disease but is not necessary in those with proctitis (although 20% of these
patients will develop proximal ‘extension’ over the lifetime of their disease).
Once-daily oral 5-aminosalicylates are the preferred first-line agents. Sulfasalazine has a higher
incidence of side-effects but is equally effective and can be considered in patients with
coexistent arthropathy. Patients who frequently relapse despite aminosalicylate drugs should be
treated with thiopurines.

Crohn’s disease
Induction of remission
Corticosteroids remain the mainstay of treatment for active Crohn’s disease. The drug of first
choice in patients with ileal disease is budesonide (9 mg once daily for 6 weeks, with a gradual
reduction in dose over the subsequent 2 weeks when therapy is stopped).
If there is no response to budesonide within 2 weeks, the patient should be switched to
prednisolone (40 mg daily, reducing by 5 mg/week over 8 weeks, at which point treatment is
stopped).
Oral prednisolone in the above dose regimen is the treatment of choice for inducing remission in
colonic Crohn’s disease.
An anti-TNF based strategy should be used as an alternative for patients, who have previously
been steroid-refractory or –intolerant. Combination therapy with an anti-TNF antibody and a
thiopurine is the most effective strategy for inducing and maintaining remission in luminal
Crohn’s patients. This strategy is more effective than anti-TNF monotherapy, which, in turn, is
more effective than thiopurine monotherapy.

Maintenance therapy
Immunosuppressive treatment with thiopurines (azathioprine and mercaptopurine) forms the core
of maintenance therapy, but methotrexate is also effective and can be given once weekly, either
orally or by subcutaneous injection.
Combination therapy with an immunosuppressant and an anti-TNF antibody is the most effective
strategy but costs are high and there is an increased risk of serious adverse effects.
Fistulae and perianal disease
For simple perianal disease, metronidazole and/or ciprofloxacin are first-line therapies.
Thiopurines can be used in chronic disease but do not usually result in fistula healing.
Infliximab and adalimumab can heal fistulae and perianal disease in many patients and are
indicated when the measures described above have been ineffective.

Surgical treatment
Indications for surgical treatment in ulcerative colitis:
• Impaired quality of life
- loss of occupation or education
- disruption of family life
• Failure of medical therapy
- dependence on oral corticosteroids
- complications of drug therapy
• Fulminant colitis
• Disease complications unresponsive to medical therapy
- arthritis
- pyoderma gangrenosum
• Colon cancer or severe dysplasia
Surgery involves removal of the entire colon and rectum, and cures the patient.

The indications for surgery in Crohn’s disease are similar to those for ulcerative colitis.
Operations are often necessary to deal with fistulae, abscesses and perianal disease, and may also
be required to relieve small or large bowel obstruction. In contrast to ulcerative colitis, surgery is
not curative and disease recurrence is the rule.