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245© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_50
Chapter 50
Miscellaneous Questions About IBD
DanielStein, SalinaFaidhalla, andAmirPatel
1. Do you ever try a second anti-TNF if the rst one didn’t work? What if the
rst one was adalimumab? What if it was iniximab?
In a primary nonresponder to adalimumab, we would try iniximab but not the
reverse. The thought is that the IV infusion and high-peak drug levels that we can
achieve with iniximab are benecial. In general, Humira seems to be underdosed
in comparison with iniximab. We have much bigger dosing exibility; with inix-
imab, you can really ramp those levels up. So, in general, if they failed iniximab,
we won’t really consider Humira. That being said, we do have some patients that are
on Humira after failing iniximab and are doing well, but it’s not something I would
do today.
Now, if a patient has had a response to one agent and then developed antibodies,
(a secondary nonresponder), we would try another anti-TNF, because there is no
overlap with the antibodies. However, we would suggest adding an IM with the
second anti-TNF.
D. Stein (*)
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical
College of Wisconsin, Milwaukee, WI, USA
e-mail: dstein@mcw.edu; ampatel@mcw.edu
S. Faidhalla
Department of Medicine Division of Gastroenterology and Hepatology, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: sfaidhalla@mcw.edu
A. Patel
Dept. of Medicine, Division of Gastroenterology and Hepatology, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: dstein@mcw.edu; ampatel@mcw.edu
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246
2. If patients are responding well to biologics, do you ever try to get them off
these drugs?
We would consider dose de-escalation, if possible, for a patient who has been in
deep remission for a long time (clinical remission is not sufcient). However, stop-
ping the medication completely will risk aring up disease, and the medication may
not be effective if restarted.
The recurrence rate after stopping biologics is about 85% in 5years.
In a large meta-analysis by Torres etal. [1], to evaluate the effect of de- escalation/
stopping immunomodulators or anti-TNFs in IBD patients, relapse rates after cessa-
tion appear high across all therapeutic classes. After stopping IM, only 15%–37%
of patients maintained clinical remission after 5years.
That meta-analysis also showed that approximately 40%–50% of patients who
discontinue anti-TNFs will experience a relapse within 2years, and studies with
longer follow-up of 7 and 10 years after withdrawal show only 35% and 12%,
respectively, remain in remission at those time intervals [2, 3].
You can consider stopping biologics in patients who are in remission and have
low drug levels, because their remission might not be drug related. This can be con-
sidered if they are in deep remission. On the other hand, for dose de-escalation, we
usually let drug level guide that.
If the patient is insisting on stopping medication: then we need deep remission,
at least two normal colonoscopies, with normal histology 2years apart before stop-
ping medication. Once the drug is stopped, we closely follow fecal calprotectin
every 6–12months and follow up colonoscopies every 2years.
In general, we do not proactively stop anti-TNFs. But if a patient has concerns
and wants to stop it, or if there’s some borderline reason to stop it, for example, if
someone is getting recurrent minor infections or recurrent UTIs where you wouldn’t
otherwise stop it, it might be worth trying.
But the caveat is that anytime you stop medications, it has to be somebody who
you trust will follow up and be willing to have surveillance colonoscopies. So, in
short, we avoid stopping biologic agents proactively and generally attempt to get
patients off immune modulators rst.
Amir Patel
It is accepted dogma that adding azathioprine to iniximab enhances bene-
t. But has adding azathioprine to adalimumab been shown to be benecial?
The original Sonic study looked at the combination of azathioprine and inix-
imab and showed efcacy. They did not study adalimumab and azathioprine. But,
more recently there was a study looking at Humira with azathioprine, which did
show superiority compared to Humira alone [4].
When I use combination therapy, I’m typically combining anti-TNFs and immu-
nologics in someone who has severe disease. So, for someone with stulizing dis-
ease or severe colitis, we use combination therapy to reduce the risk of developing
antibodies, and we know that adding the immunologics to the anti-TNFs can also
boost the drug levels.
D. Stein et al.
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If a patient fails an anti-TNF in ulcerative colitis, it is my impression that
ustekinumab is a good second choice, JAK inhibitors are a good second choice,
but vedolizumab doesn’t work. Do you agree?
I would ask: what is the severity of disease and what is the context? Entyvio is a
great drug. It just doesn’t have a lot of good induction data. It works slower. So
that’s why, if speed is of the essence in treating someone’s disease, a lot of us will
probably go toward an IL-23 or a JAK inhibitor as our second line.
Is your opinion about Entyvio as second-line treatment for patients who fail
anti-TNFs in Crohn’s the same as for UC?
A lot of us have the opinion that Entyvio works better for colonic disease. So, if
someone has a stricture in the ileum or stulizing disease, then Entyvio would not
be our preferred choice.
Is iniximab superior to adalimumab in UC and in Crohn’s?
There’s been no head-to-head study looking at that question, but I would say that
for ulcerative colitis, Remicade is probably superior to Humira. A lot of that is
because with Humira, you’re just giving a at dose, while with Remicade, you can
adjust the dose by weight. And some of these patients will have a protein-losing
enteropathy, where they’re losing albumin and protein and potentially the drug
itself. So, for ulcerative colitis, I would say that there’s no question Remicade is
superior.
For Crohn’s disease, I guess it would depend on the context of the disease itself.
So, if someone came to me and they had stulizing disease and had multiple
surgeries, then I would say, yes, Remicade is probably going to be a superior drug
for that same reason and that you can give them a dose based on their weight and
adjust it easier. The problem with Humira has always been that the only adjustment
you can make is giving it weekly or every 2weeks.
And the data on therapeutic drug monitoring with Humira is not as well validated
as it is with Iniximab. That’s why Remicade, in our opinion, has always been supe-
rior to Humira, in which you can always adjust the dose. They can get 10mg every
4weeks, or every 8weeks. Some of us have gone as high as 15mg every 4weeks
just to get them at this nice therapeutic drug range. A lot of us would probably say
that Remicade is superior to Humira.
Do you feel relatively safe using AZA in young males for periods under
2years?
Yes, I think I feel safe doing that. And a lot of that relates to the context of the
disease. So, if a young man comes to me and he’s had multiple surgeries and a his-
tory of stulas, there’s no question; I’m going to give him combination therapy,
because the risk of the untreated disease far outweighs the small risk of that rare
hepatosplenic T cell lymphoma.
Another question, and it’s along a similar narrative, is when can we de-escalate
therapy. So, for someone on combination therapy, when can we stop the azathio-
prine? And a lot of us would do it after 2years, but there have been some recent
studies on de-escalating therapy within a year.
50 Miscellaneous Questions About IBD
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248
So, someone’s on combination therapy, and they’re doing great. The colonos-
copy shows deep remission, where they don’t have any activity endoscopically or
under the microscope. Then, the question is, can we just stop the azathioprine? And
some of us will do that and that’ll be based on drug levels.
Where do you stand on the newer drugs? How much do ozanimod, risanki-
zumab, and upadacitinib add to the mix? Do you think they are a good
addition?
Yes, a lot of the experts are very optimistic, particularly about risankizumab and
upadacitinib. As a result, we have been using them a lot. In one of your earlier
cases—the young lady with proctitis who didn’t want to take suppositories—I was
going to say that if she’s away at college, you can offer her some of these new oral
therapies, like ozanimod (Zeposia), tofacitinib (Xeljanz), or upadacitinib (Rinvoq).
She would’ve been a perfect candidate for ozanimod because she was just failing
mesalamine. And the studies actually looked at a subset of patients with colitis who
had failed mesalamine, and patients on Zeposia did very well.
The reason why we’re enthusiastic about Skyrizi and Rinvoq is because a lot of
the studies these days are not only looking at how these patients respond clinically
but how they respond histologically and endoscopically. So, more of the studies
over the last decade have looked at mucosal healing as an endpoint, because we do
know that if you can achieve that deep remission, it reduces the risk of ares, hos-
pitalizations, and colon cancer risk, and some of the data on Skyrizi and Rinvoq
have shown early induction data and the ability to heal the mucosa.
A lot of IBD experts are considering the use of Skyrizi rst line for Crohn’s dis-
ease and Rinvoq rst line for ulcerative colitis. But we have to remember, Rinvoq
right now is being marketed only for patients with colitis who have failed anti-TNF
Is vedolizumab a godsend because of its lack of side effects and concerns? Is
it strong enough?
Yes, vedolizumab is a great drug because of its safety prole, but I think that the
induction therapy is what concerns a lot of us. It takes a certain type of patient to
consider Entyvio, someone with moderate ulcerative colitis or moderate Crohn’s
disease who isn’t on the verge of needing surgery. Also, older patients who typically
don’t present with a severe disease are candidates for Entyvio. But the question is,
will the therapy work? And I don’t think we have an answer for that, but we’re look-
ing into data and doing studies, where maybe we can do a blood test or have a stool
sample or a mucosal sample that could inform us whether this person is going to
respond to anti-TNF or that person’s going to respond to anti-integrin therapy.
But we’re not there yet. Hopefully, we’ll get there soon. But yes, I think Entyvio
is a great drug. It just depends on the person that I’d use it on. So, for someone who
has severe disease, heading for surgery, I probably wouldn’t use it. But if their dis-
ease is on the more moderate side, then, yes, I would.
Daniel Stein, Salina Faidhalla
Do you see any differences in the ways you manage IBD from the way gas-
troenterologists in the community do? Are there any general recommendations
you would make?
D. Stein et al.
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249
Yes, there are a few. First, we see too much use of mesalamine in patients with
Crohn’s disease. Second, we nd that community practitioners are occasionally too
conservative with their treatment. Part of this may be an under-recognition of the
severity of the disease. In addition, community practitioners tend to be hesitant to
use advanced therapies. Although there are some risks with the use of advanced
therapies the risk/benet ratio remains quite low. Biologics, including the small
molecules, should be strongly considered in patients with IBD who have moderate
to severe disease.
We also see many UC patients treated with adalimumab, which is usually not a
rst choice for us; we prefer iniximab.
And, nally, we think there is some under-recognition of primary nonresponse,
dened as no signicant improvement without the aid of steroids. Too often patients
are continued on agents for long periods of time despite being ineffective or requir-
ing repeated doses of steroids.
References
1. Torres J, Boyapati RK, Kennedy NA, Louis E, Colombel JF, Satsangi J. Systematic review
of effects of withdrawal of immunomodulators or biologic agents from patients with inam-
matory bowel disease. Gastroenterology. 2015;149(7):1716–30. https://doi.org/10.1053/j.gas-
tro.2015.08.055. Epub 2015 Sep 14.
2. Steenholdt C, Molazahi A, Ainsworth MA, Brynskov J, Østergaard Thomsen O, Seidelin
JB.Outcome after discontinuation of iniximab in patients with inammatory bowel disease
in clinical remission: an observational Danish single center study. Scand J Gastroenterol.
2012;47(5):518–27. https://doi.org/10.3109/00365521.2012.660541. Epub 2012 Mar 1.
3. Waugh AW, Garg S, Matic K, Gramlich L, Wong C, Sadowski DC, Millan M, Bailey R,
Todoruk D, Cherry R, Teshima CW.Maintenance of clinical benet in Crohn’s disease patients
after discontinuation of iniximab: long-term follow-up of a single Centre cohort. Aliment
Pharmacol Ther. 2010;32(9):1129–34.
4. Matsumoto T, Motoya S, Watanabe K, Hisamatsu T, Nakase H, Yoshimura N, Ishida T,
Kato S, Nakagawa T, Esaki M, Nagahori M.Adalimumab monotherapy and a combination
with azathioprine for Crohn’s disease: a prospective, randomized trial. J Crohn's Colitis.
2016;10(11):1259–66.
50 Miscellaneous Questions About IBD
https://t.me/medicina_free
Part III
Disorders of Gut–Brain Interaction
https://t.me/medicina_free
253© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_51
Chapter 51
Introduction to Disorders of Gut-Brain
Interaction
W.HarleySobin
The challenges of treating IBS-D, IBS-C, functional constipation, functional dys-
pepsia, bloating, and functional abdominal pain are discussed in multiple case pre-
sentations. A thorough review of medications, dietary therapy, and the interplay
between anxiety, depression, and severity of symptoms is presented.
The use of eluxadoline, alosetron, rifaximin, IBgard, linaclotide, lubiprostone,
prucalopride, buspirone, mirtazapine, and other drugs is reviewed. Tests involved in
the diagnosis of these functional syndromes are discussed. Bloating, distension, and
the interplay with the viscerosomatic reex are explained. Tips for managing pain-
ful gas are outlined as well as the use of antidepressants in treating these patients
and how to manage abdominal cramping.
Other issues covered in these case discussions include the following: Is it neces-
sary to perform a colonoscopy to diagnose IBS-D? What other tests should be
ordered in the patient with presumed IBS-D? What tests may be helpful in a patient
with severe constipation? How best to manage constipation in a patient on chronic
opiates, or a patient with possible outlet dysfunction. How to manage functional
dyspepsia both postprandial distress syndrome (PDS) and epigastric pain syndrome
(EPS) and how to treat abdominal wall pain.
Multiple causes of bloating are discussed along with potential therapies. The use
of central neuromodulators in treating patients with hard-to-manage disorders of
gut-brain interaction is discussed at length.
W. H. Sobin (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: hsobin@mcw.edu
https://t.me/medicina_free
255© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_52
Chapter 52
IBS-D
W.HarleySobin andPatrickSanvanson
Case 1 A 32-year-old female presents with a history of weekly recurrent loose
bowel movements over the past year, along with associated abdominal cramps. She
works as a paralegal in a high-pressure law rm. She is on no medicines. Her fre-
quent bathroom trips during the work day are now embarrassing her, so she sees
her primary care physician. Her exam is unremarkable. Labs reveal a normal CBC,
CRP, TSH, iron panel/ferritin, and fecal calprotectin. Her primary care doctor
thinks she has IBS-D but is worried she might have inammatory bowel disease
(IBD) and sends her for a second opinion, asking whether she should have a
colonoscopy.
Is a colonoscopy necessary to rule out IBD and diagnose IBS?
No, the normal lab results all weigh against the diagnosis of IBD.The history,
physical exam, and labs are all consistent with the diagnosis of IBS-D.A colonos-
copy is not necessary at this time to conrm this diagnosis.
Are there other labs necessary to evaluate the patient before treating her?
Celiac serology is indicated in the evaluation of patients with suspected IBS-D
[1, 2]. On occasion, we will obtain an abdominal X-ray upon initial presentation to
conrm there is not an excessive stool burden and that we are not dealing with an
overow diarrhea situation.
Celiac serology returns negative. Abdominal X-ray demonstrates no increased
stool burden. You suggest dietary manipulations, including avoiding caffeine, lac-
tose, articial sweeteners, and processed meats, which does not help much. You
discuss a low-FODMAP (fermentable oligosaccharides, disaccharides, monosac-
charides, and polyols) diet, which she tries but also gets no benet from this
W. H. Sobin (*) · P. Sanvanson
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: hsobin@mcw.edu; psanvans@mcw.edu
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256
intervention. You have prescribed Imodium (loperamide), which helps a little bit
with the diarrhea but not the cramping. She is worried about taking this on a chronic
basis, even though you assure her that it is okay.
What other treatments can you consider?
We may try psyllium-based ber to see if it helps with regulating stools.
Antispasmodics, like dicyclomine and hyoscyamine, have been part of our general
armamentarium for decades. However, studies proving their efcacy are limited.
The latest ACG (American College of Gastroenterology) guidelines [1] did not sup-
port their use, although more recent AGA guidelines [3] did. In our practice, we
continue to use antispasmodics in younger patients. We worry more about their
anticholinergic side effects in the elderly and are reluctant to use them in those
patients. Other drugs that we will try include eluxadoline (Viberzi) [4], peppermint
oil in the form of IBgard [5], rifaximin [6], cholestyramine [7, 8], and alose-
tron [9–11].
Eluxadoline [4] works on opioid receptors to decrease bowel frequency and
abdominal pain, and we nd that it helps a few of our patients with IBS-D.It is
contraindicated in patients who have had a cholecystectomy. If we have a patient
with presumed IBS-D who has had a cholecystectomy, we will always try cholestyr-
amine rst or obtain a 48-h stool collection for bile acids. Many of these patients
will have bile-salt-related diarrhea and respond to this treatment [7, 8]. However, if
the patient has an intact gallbladder, no past history of pancreatitis, and is not a
heavy drinker, we will try eluxadoline.
IBgard is another drug worth trying [5]; it is an OTC medication containing pep-
permint oil. Rifaximin [6] will work to relieve symptoms in some patients with
IBS-D.This is particularly true if your patient has had reason to have a hydrogen
breath test and the results were consistent with SIBO.A breath test is not required
before trying rifaximin, but it is those patients with IBS-D and a positive breath test
who are most likely to respond. However, rifaximin is quite expensive, requires
repeat treatment, and is often not covered by insurance. When starting any new IBS
therapy, we ask patients to give us an update in 2–4weeks.
The patient tries dicyclomine, eluxadoline, IBgard, and even rifaximin without
much benet. She describes her frustration to you and expresses feelings of hope-
lessness and anxiety and says she is starting to feel depressed.
What is the association between anxiety, depression, and IBS, and how do
you manage it?
For patients with debilitating IBS, we let them know that we do not think their
physical symptoms are simply manifestations of depression. There are several
points we emphasize. First, it is natural to experience feelings of anxiety and even
depression when physical symptoms continue unabated. Second, as physical symp-
toms continue, they tend to get embedded in the patient’s psyche and lead to soma-
tization, where a patient becomes obsessed with those physical symptoms. It is also
common for patients to catastrophize, thinking in terms of gloom and doom regard-
ing their ailments. We will typically try getting these patients to see a mental health
provider, who provides the tools to help with these unhelpful behavioral patterns.
W. H. Sobin and P. Sanvanson
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257
Cognitive behavior therapy is particularly useful in many of these patients [12].
Learning that they can control their thought processes can also benet the level of
their IBS.
Will you ever prescribe antidepressants for these patients?
We are comfortable using tricyclics in patients with IBS-D [13] as central neuro-
modulators, not as antidepressants. Using a relatively low dose of nortriptyline
helps decrease diarrhea and abdominal pain [14]. The dose we’re using is much less
than the usual antidepressant dose. We usually don’t prescribe an SSRI in IBS-D,
because SSRIs tend to increase diarrhea (with the exception of paroxetine (Paxil),
which is somewhat constipating but has a number of problems associated with its
use). Our tricyclic of choice is nortriptyline. We think it is better tolerated than ami-
triptyline. But in patients with severe diarrhea, amitriptyline may be preferable.
When we prescribe these drugs, we tell the patient that we are not using them to
treat depression; we are giving them to treat the brain-gut connection that is out of
kilter in IBS.Prior to starting a tricyclic, an EKG is obtained to conrm the absence
of baseline QTc prolongation and is subsequently monitored with dose adjustments.
The patient is placed on nortriptyline 25mg at bedtime, which is then increased
to 50mg. Her symptoms do improve. She is pleased that she is feeling somewhat
better but wonders if there are any other specic GI drugs that might benet her.
One other medicine worth considering is alosetron [9–11]. This is approved only
for females with IBS-D who have failed other therapies. We have had some great
success using alosetron in women with intractable symptoms of IBS-D. We do
review the background history of the drug with our patients. It was taken off the
market years ago because of cases of severe constipation and cases of bowel isch-
emia. But, at that time, the drug was being given in higher doses and being used in
older patients who probably should not have been receiving it in the rst place. So,
now, we use lower doses and avoid its use in anyone who is at increased risk of
ischemic colitis.
After trying alosetron, at the dose of 0.5mg twice daily, the patient quickly feels
marked relief of her diarrhea and abdominal pain. After a month on the medicine,
she feels back to normal. You gradually taper her off of the nortriptyline while main-
taining on alosetron. After tapering nortriptyline off, she has some increased diar-
rhea that rapidly responds to an increase in alosetron to 1mg bid.
Case 2 A 43-year-old female presents with increased abdominal cramps and diar-
rhea over the past 8months. She gives a long history of frequent, somewhat soft,
bowel movements since she was in her 20s. The fact that she moved her bowels 2–3
times a day never bothered her. One year ago, she divorced her husband of 22years
after learning of an affair he was having. Since then, she has been having increased
abdominal cramps, along with even looser stools. There is no blood in her stool. She
takes no medications. She has no surgical or other past medical history. On the
physical exam, she winces when you press on her abdomen, but you think it is
abdominal wall pain. Indeed, you do a Carnett test and it is positive. Her exam is
otherwise negative. You decide to order a CBC, CRP, fecal calprotectin, iron panel/
ferritin, and celiac panel. These tests all return negative.
52 IBS-D
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