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SEATTLE,
WA--Every gastroenterologist has IBD patients who fail to improve
despite appropriate standard therapy. "We have to learn to
think outside the box as to why a patient is not responding to therapy.
We may simply be using the wrong treatment, Sunanda (Susie) Kane,
MD, said at the annual meeting of the American College of Gastroenterology.
If a patient is not responsive to 5-ASA, for instance, she may be
hypersensitive to this class of drugs. "It turns out that there's
a 5-ASA hypersensitivity rate of between three and seven per cent
(Dubinsky et al Gastroenterology 2002;122:904-15], which means patients
will actually get worse on an oral dose or an enema," noted
Dr. Kane, Professor Assistant Professor of Medicine, Division of
Gastroenterology, University of Chicago's Pritzker School of Medicine.
"Ask yourself
whether the disease is actually progressing or if the patient might
be hypersensitive. And the only way to find out clinically is to
stop the 5-ASA and see where the disease goes from there."
Some patients also exhibit 6-MP resistance. "You can push the
dose to 4 mg/kg and they are still not responding. They may be resistant
and so you have to think about other treatment modalities."
Intriguing early work points to the existence of corticosteroid
resistance. "We've all seen those patients who are on 60mg
of prednisone a day but are not responsive to these high doses."
A recently identified genetic marker, the GS receptor beta, appears
to predict corticosteroid resistance (Honda et al Gastroenterology
2000;118:859). Some patients may have multidrug resistance to drugs
such as methotrexate and cyclosporine. "The same genes that
place a patient at risk for expression of the disease will also
help us target our therapies for the disease."
Another cause of refractory IBD could be undertreatment. "Our
patients may be tolerating the 5-ASA, for example, but perhaps we're
not pushing the dose as high as we should. It may be that adding
topical therapy, which seems to have a higher induction rate, would
be better than just pushing the oral dose."
While the FDA recommends a 5-ASA dose of 2.4 g/d, clinicians usually
raise that to 4.8 g, and current clinical trial that are using 6
g/d and are noting a dose response. "We know clinically that
pushing the dose to 4.8 increases efficacy without an increase in
toxicity," Dr. Kane said.
Physicians may also be erring on side of undertreating patients
with immunosuppressants. "Controlled trials of azathioprine
at doses of 2 to 3 mg/kg/d and of 6-MP at 1.5mg have rarely shown
a 6-TGN level of 235. (Greater than 235 is considered indicative
of a therapeutic dose.) TPMT deficiency does lead to increased levels
of 6-MP over 6-TGN, and in these patients we need to look at TPMT
activity as well as marker levels," she said. The use of 5-ASA
can actually inhibit TPMT activity. "You can look at that as
a glass half full or half empty- it can be a good or a bad interaction."
Another issue in refractory IBD is compliance. "If a woman
is thinking about getting pregnant, her gynaecologist may have told
her to go off all her medications, and medications are effective
only if delivered to the body," Dr. Kane said. Multiple studies
have shown a 40 to 60 per cent non-adherence rate to IBD regimens,
"no matter how much time you've spent with the patients and
how much you think you've bonded with them."
For two years, Dr. Kane and colleagues followed a cohort of 98 ulcerative
colitis patients on mesalamine, of whom 31 experienced clinical
recurrence (Kane et al Am J Med 2003;114(1):39-42). During
the study period, 60 per cent fit the definition of non-adherence.
"That is, they took less than 80 per cent of the medication
prescribed. We actually called their pharmacies and tracked refill
data," Dr. Kane said.
Another question that must be posed is: does the patient really
have active IBD? "We must elicit from the patient inflammatory
versus irritability symptoms." Nocturnal bowel movements go
with inflammation, while cramps and bloating that are relieved by
a bowel movement mean irritability. "Get them to describe whether
they have real pain or more bloating and discomfort, and also think
about a concurrent diagnosis."
Dr. Kane stressed that some patients could well have concurrent
disease. "IBS is very prevalent, and many of the symptoms of
IBS and IBD overlap." Reporting on an IBD population, the ACG's
"Red Journal" supplement stated that one-third of UC patients
and more than half of Crohn's patients met Rome II criteria for
IBS as well (Simren et al, Am J Gastro 2002;97:279-83).
Dr. Kane conceded that in the past few months she herself has had
occasion to re-diagnose UC as a single rectal ulcer. Several UC
patients experienced some rectal bleeding and some fecal urgency.
On endoscopy, certain individuals had what looked like erythema
and some had nonspecific colitis. Others had a long history of strained
bowel movements and constipation. "In some cases we need to
rethink the diagnosis of UC. Is the patient who started out with
UC converting to Crohn's? Should we be thinking about other kinds
of therapies if this is the case?"
In female patients, there are gender-specific issues. "There
can be a normal cyclical variation in irritability and disease activity
during the menstrual cycle," she said. Moreover, physicians
should not ignore the role of other pelvic organs. "I'm embarrassed
to say that I've had some young women come in with right- or left-sided
lower abdominal pain and I didn't even think about the possibility
of ovarian cysts. It turned out they had a rupturing of very large
cysts, which was causing their pain." Endometriosis and pelvic
inflammatory disease are other potential sources of chronic abdominal
pain.
Yet another variable is NSAID use. A study by Felder and colleagues
found a recent positive history of NSAID use in 31 per cent of 60
patients hospitalized for IBD flare-ups. In a control IBS group,
only three per cent had used NSAIDS in recent weeks (Am J Gastro
2000;95(8):1949-54).
A patient with refractory disease may also have a simple infection,
Dr. Kane said. Even if a patient is free of pathogens or parasites
at time of diagnosis, she may have a recurrent infection now, or
food poisoning with Salmonella or Shigella. "Check for CMV
and C. difficilis and in paediatric cases for rotavirus," she
said.
Dietary indiscretions may play a role. Symptoms can be worsened
by high-residue foods, for example. In addition, a woman wishing
to conceive may have stopped smoking on her doctor's orders. Patients
who have gained weight on prednisone, for example, may turn to dietetic
foods containing sugar substitutes such as sorbitol, which can cause
diarrhea, though not necessarily bloody.
"Then there's the big black box of herbal therapies,"
Dr. Kane said. "Patients are not telling us what they take
beyond the prescriptions we give them. "While some of these
alternative treatments may be safe and even efficacious, some are
harmful. So if your patient is not doing well and her disease is
active, ask her what else she's taking."
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