Desensitisation of ulcerative colitis patients intolerant for mesalazine treatment.

Mesalazine (= 5-aminosalicylic acid, 5-ASA) is used in the treatment of
inflammatory bowel disease; Crohn's disease and ulcerative colitis.
Particularly in mild, moderate active ulcerative colitis mesalazine is a first
choice drug approach. Remission may occur in up to 50-71% of patients with mild
ulcerative colitis within 4 weeks after starting mesalazine treatment.
Long-term remission is possible in 65-78% of patients receiving mesalazine.
Furthermore, mesalazine is a safe drug that may avoid use of prednisone for
exacerbations of ulcerative colitis. This may decrease chance of known severe
prednisone side effects as osteoporosis or type 2 diabetes mellitus. The
anti-inflammatory effect may also reduce risk on development of colon cancer,
as ulcerative colitis patients may be at higher risk. Side effects for
Mesalazine are not rare. Several case reports report that oral desensitization
with 5-ASA products is possible for patients with a known history of side
effects of 5-ASA. Mechanisms behind successful desensitization are yet to be
identified. Until now, effective desensitization is primarily described in
patients intolerant of oncologic medication.

Primary endpoint:
- Successful desensitization for Mesalazine in ulcerative colitis patients with
a presumed history of intolerance for Mesalazine.

Secondary endpoint:
- To investigate if a presumed intolerance for Mesalazine may be reproducible
in a clinical setting.
- Describe the pattern of intolerance for Mesalazine in patients with
ulcerative colitis.

This study is a dual-center, prospective, double-blind study. Furthermore, the
patients will be randomized in the first part of the study, either to a
re-challenge with placebo or Mesalazine. Patients with ulcerative colitis and a
well-documented history of intolerance for mesalazine will be included.
Patients will be split in two groups based on symptoms of intolerance
(objective or subjective symptoms). Objective signs of intolerance are: mild
acute pancreatitis, fever >38.0 C, CRP increase of more than 30 mg/L and
urticaria. Subjective symptoms include (an increase of) secretory diarrhea.
Medical history, blood tests and skin tests (see below) will be made in
advance. This will be done in cooperation with the pulmonologist and/ or
allergist. The skin tests will be performed with pure Mesalazine. After
inclusion, informed consent and skin tests, the patient will start the first
part of the study. This will be a double-blind placebo controlled re-challenge
with Mesalazine or placebo, performed in a clinical setting. The re-challenge
is to asses whether or not the presumed intolerance will be reproducible. The
total duration of the re-challenge will take a total of 9 weeks.
Patients will be given strict orders to discontinue the medication as soon as
they experience complaints. Furthermore, the principal investigator should be
contacted and notified. Laboratory tests will be carried out, and if necessary,
physical examination (see Table 1.). In addition, laboratory test will be
carried out in patients who experienced no symptoms after the first week. After
that, a wash-out period of 4 weeks will be followed by a second re-challenge.
Again with either placebo or mesalazine and followed by laboratory tests. If
the patient is able to reproduce the intolerance pattern for a second time, a
hospital admission for two days will be administered for the desensitization
procedure.

Mesalazine is a registered drug.
Reported adverse reactions that may occur during rechallenge and/ or
desensitization are as previously described: acute (mild) pancreatitis,
bronchospasm, fever, secretory water, rising/elevated CRP, urticaria. These
risks are minimal and acceptable. Adverse effects are most likely to be
identical to earlier reaction or not likely to occur at all. Patients with
previous severe intolerance reactions as anaphylaxis, bullous skin disorders,
bronchospasm and interstitial nephritis are not included in this study.