refractOry prOctItIS: HOw tO ManaGe It 135

135
Refractory proctitis: How to manage it
James Lindsay
UK
Learning objectives
1.Patient with proctitis should be treated with evidence based
topical therapy and oral steroids if required.
2. Patients with refractory proctitis require a thorough history of
their symptoms, medication history and adherence
3.Initial assessment to confirm diagnosis and exclude alternative
diagnoses should include stool culture / C. difficle toxin, endoscopy and histology
4.Therapy with intravenous steroids, Infliximab, oral / rectal ciclosporin or tancrolimus can be considered
5. Open label evidence exists for many other topical therapies but
local availability will vary
6.Only treatment that delivers clinical remission should be continued.
1. Initial management of proctitis
2.Investigation of patients with symptoms refractory to conventional management
3. Differential diagnosis of refractory proctitis
4. A systematic approach to managing refractory proctitis
The Montreal classification defines ulcerative proctitis as macroscopic colitis extending no further than the recto-sigmoid junction, although some patients may also have a patch of inflammation in the caecum. Patients typically present with the frequent
passage of blood and mucous associated with urgency, tenesmus
and occasionally incontinence; this may be separate or associated
with the passage of formed stool. Proximal constipation may lead
to abdominal discomfort and bloating. Symptoms can have a marked effect on the patient’s quality of life. A full medical history
should be taken in all patients and include extra-intestinal manifestations, recent travel, contact with enteric infectious illnesses, medication (including antibiotics and non-steroidal anti-inflammatory drugs), smoking habit, sexual practice, family history of IBD,
family history of CRC and previous appendectomy. Initial investigations should include endoscopy, stool culture and routine blood
tests. Biochemical markers of inflammation such as the CRP do
not correlate well with disease activity in proctitis. An ileo-colonoscopy is recommended in all patients to delineate the full extent
of disease in patients whose initial diagnosis was made at sigmoidoscopy. Up to 30% of adult patients with ulcerative colitis have
proctitis at diagnosis. The incidence of proctitis is lower in patients
presenting in childhood who more frequently have extensive disease. Proximal extension of disease may occur during the disease
course and must be considered as a cause of symptoms refractory
to standard topical therapy. Consensus based guidelines for the
management of Ulcerative colitis including proctitis published by
the European Crohn’s and Colitis organisation were published in
2006 and have recently been updated. Initial management of proctitis The first line therapy for proctitis is 1g topical mesalazine
(5ASA) daily administered as a suppository. A recent Cochrane
database systematic review confirmed the superiority of this therapy over placebo for inducing symptomatic, endoscopic and histological response and remission. The pooled odds ratio (POR) for
symptomatic remission was 8.3 (8 trials, 95% CI 4.28 to 16.12; P
< 0.00001). There is no value in increasing the dose of suppositories above 1g daily and once daily therapy is equally effective as divided doses. Suppositories are more appropriate than enemas in
patients with proctitis as they target the site of inflammation. Topical mesalazine is at least twice as effective as topical steroids
whether for symptomatic or endoscopic response and therefore
Medical & Surgical Gastroenerology II Medical / surgical scenarios in ulcerative colitis
Saturday, October 22
14:00 – 16:30
Key messages
136
James Lindsay | Refractory proctitis: How to manage it
Saturday, October 22
14:00 – 16:30
topical steroids should be reserved as second line therapy for patients who are intolerant of topical mesalazine. Although topical
mesalazine is more effective than oral mesalazine alone the combination of oral and topical mesalazine may be more effective than
either alone although there has been no trial that examines this in
patients with proctitis alone. Combining topical mesalazine and
topical steroids may also be effective. Patients who fail to improve
on oral / topical mesalazine and topical corticosteroids should be
treated with the addition of oral prednisolone. Refractory proctitis The ECCO consensus statement defines refractory proctitis as
persistent symptoms due to colonic inflammation confined to the
rectum despite treatment with oral steroids and oral / rectal 5ASA
for 6-8 weeks. Refractory proctitis is a common and often troublesome clinical dilemma with a huge impact on quality of life for the
patient. There are few appropriately controlled rigorous clinical
trials that include patients in this specific situation, and therefore
clinical evidence of therapeutic benefit often has to be derived
from small open label clinical trials. However, a coherent therapeutic strategy is needed if patients are not to get frustrated by
persistent symptoms and frequent alterations to ineffective therapeutic regimens. It is clearly important to consider and identify the
aetiology of the refractory disease course. One obvious explanation is that the rectal inflammation is not responsive to the prescribed medication. However, alternative explanations include:
1. Poor adherence to prescribed therapy
2.Delivery of an inadequate concentration of the medication to
the affected inflamed mucosa
3. Unrecognised complications (such as proximal constipation or
co-existent infection)
4.Inappropriate initial diagnosis / secondary condition in addition to ulcerative proctitis (see Table 1)
Initial assessment The initial step is to review current symptoms
and treatment to date. It is important to be clear that the clinical
scenario is attributable to active proctitis and that the patients have
definitively failed an appropriate course of conventional evidence
based therapy. This should be followed by a careful discussion
about adherence to the prescribed medication. Individual patients
may find specific preparations easier to use and therefore tailored
prescribing based upon a sound knowledge of the wide range of
formulations available may increase adherence. The next step is to
reassess the extent and activity of the proctitis and exclude alternative diagnoses such as those listed in table 1. This will always require stool culture, endoscopy and biopsy. An abdominal x-ray can
be useful to diagnose proximal constipation; since abnormal intestinal motility induces proximal colonic stasis in patients with distal colitis which may affects drug delivery and also be a cause of
abdominal discomfort and bloating. If there is visible faecal loading a laxative should be considered. Finally more detailed investigation as listed in table 1 may be required in specific cases depending on the clinical scenario. Medical therapy The goal of medical
therapy for refractory proctitis includes induction and then maintenance of clinical remission. Consideration should be given to
admission for assessment and intravenous steroid therapy which
has been reported to induce remission in a significant number of
patients. Alternatively, there is open label evidence, often from retrospective case reviews, supporting the use of salvage medical therapies such as oral or rectal ciclosporin, oral or rectal tacrolimus,
and infliximab. A clear discussion about the quality of the evidence
supporting these therapies and the potential side effects is essential. Once clinical remission is achieved patients are likely to require
maintenance therapy with azathioprine. Some patients may choose
to continue infliximab if it has achieved remission as a maintenance either as monotherapy or in combination with a thiopurine.
Immunosuppressive therapy that does not result in clinical remission should not be continued. If disease persists in spite of these
approaches, surgery is likely to be the outcome, but if the patient is
not acutely ill then the decision should never be precipitate and a
range of topical or anecdotal therapies are available. Alicoforsen
enemas, a novel topical biological therapy, have shown benefit in
distal colitis in placebo controlled phase II trials with sustained
clinical improvement and are now available for clinical use. They
contain an antisense oligonucleotide designed to inhibit the production of human ICAM-1 protein inhibiting leucocyte adherence, migration and activation. However there are no controlled
trials in a defined population with refractory proctitis. Placebo
controlled trials have suggested a benefit of short chain fatty acid
enemas although difficulties with production and availability limit
their widespread use in Europe. Historical small open label trials
have suggested benefit from alternative topical therapies such as
lidocaine enemas, acetarsal suppositories, Epidermal Growth Factor enemas, and transdermal nicotine patches. The choice depends
on local availability and personal preference, since many have to be
made up individually by the pharmacy. Finally, there is evidence
from retrospective cohort studies that appendicectomy may improve outcome in patients with refractory proctitis. Clinical judgement and an honest appraisal about the impact of symptoms on
the quality of life or employment are necessary. Surgery Surgery
for refractory proctitis requires an initial subtotal colectomy and
ileostomy. Patients may still be troubled by inflammation in the
rectal stump and can proceed to a restorative ileoanal pouch or
completion proctectomy and permanent ileostomy. Up to 10% of
patients who have a colectomy for refractory UC only have distal
disease. The outcome of colectomy and pouch formation for distal
colitis is usually good with a significant decrease in daytime and
nocturnal stool frequency after surgery. This also removes the risk
of future dysplasia and colorectal cancer. Reported patient satisfaction is high, with many commenting that they wished they had had
the surgery sooner.
References
No references
Policy of full disclosure
James Lindsay is on the UK advisory board for Abbott, Ferring,
MSD and Shire pharmaceutical companies. He is on the international steering group for Atlantic Pharmaceutical Ltd. He has received honoraria for speaking from Abbott, Ferring, MSD, Shire, and
Warner Chilcott. He has received investigator initiated research
Medical & Surgical Gastroenerology II Medical / surgical scenarios in ulcerative colitis
Refractory proctitis: How to manage it | James Lindsay 137
grants from MSD and Shire and service support grants from Abbott, MSD and Shire.
Alternative Diagnosis
Feature on history /
examintaion
Investigation required
Haemorrhoids
Post defecatory
bleeding and proctalgia.
Skin tags
Rectal exam and
proctoscopy
Anal Fissure
Marked proctalgia with
some blood / mucous
discharge
Rectal exam and
proctoscopy
Crohnʼs disease of
rectum
Perianal disease + other
symptoms of Crohn`s
disease
Full endoscopic and
radiological assessment
and histology
Radiation proctitis
Previous radiation
therapy
Sigmoidoscopy
Mucosal prolapse /
Solitary rectal ulcer
syndrome
Constipation / evacua­
tory abnormality
Sigmoidoscopy with
typical histology
Rectal cancer
Family history, age,
duration of colitis.
Palpable mass
Sigmoidoscopy and
histology
Clostridium difficile
co-infection
Recent hospilisation /
antibiotic therapy
Stool toxin assay, sigmo­
idoscopy and biopsy
CMV colitis after
steroid therapy
Flare of disease once on
steroids
CMV lgG confirms prior
exposure, histology will
confirm diagnosis
Infection (gonorrhoea /
lymphogranuloma
venereum – LGV)
Appropriate contact
history, inguinal lymph­
adenopathy
Microscopy and culture
of rectal swab / serology.
Medical & Surgical Gastroenerology II Medical / surgical scenarios in ulcerative colitis
Saturday, October 22
14:00 – 16:30
Table 1: Differential diagnosis for patients with refractory
proctitis