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211© 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_35
Chapter 35
Ustekinumab vs Risankizumab inCrohn’s
DanielStein andSalinaFaidhalla
A 28-year-old female smoker is found to have mild moderately severe Crohn’s coli-
tis without obvious small bowel involvement. She does not want to go on an anti-
TNF and is wondering about going on ustekinumab or the new drug risankizumab.
Can you discuss how you would choose between ustekinumab and risanki-
zumab if insurance coverage was not an issue.
Ustekinumab is an IL-12 and IL-23 inhibitor while risankizumab is an IL-23
inhibitor alone. Risankizumab was recently approved for use in moderate-to-severe
Crohn’s disease. It has endoscopic and histologic data supporting its efcacy.
Both medications start with IV infusion for induction followed by SQ injections.
They have good efcacy and comparable side effect proles; however, there are not
enough data comparing the two medications since risankizumab was only recently
approved. The safety prole overall appears to be similar; there might be a small
risk of DILI with risankizumab since one patient developed liver injury in the trial.
Risankizumab may have increased efcacy compared with ustekinumab and
clinically may be comparable to iniximab. Our clinical experience with risanki-
zumab in Crohn’s patients who failed multiple biologics has been similar to what
was seen in the clinical trials. If insurance is not an issue, then we would generally
choose risankizumab.
D. Stein (*)
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical
College of Wisconsin, Milwaukee, WI, USA
e-mail: dstein@mcw.edu
S. Faidhalla
Department of Medicine Division of Gastroenterology and Hepatology, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: sfaidhalla@mcw.edu
https://t.me/medicina_free
212
In comparing vedolizumab, ustekinumab, and risankizumab in Crohn’s
disease, what is your rst choice, or which drug do you prefer in which
situation?
Many factors, including age, disease severity, disease behavior (inammatory,
stricturing or stulizing), location, the presence of perianal disease, extraintestinal
manifestations, prior biologic exposure, history of malignancy, serious infections,
and patient preference, play a role in choosing a biologic and must all be considered
carefully.
VDZ is usually used to treat moderate-to-severe Crohn’s patients with no extrain-
testinal manifestations, and no perianal disease since it is more gut selective. This is
also a good choice in patients with a history of malignancy or serious infections
given its favorable side effect prole. However, it does have a slower onset of action
and possible delayed clinical response when compared to anti-TNF or UST.
That being said, there are some data supporting VDZ use in perianal disease. The
exploratory analysis from the GEMINI 2 trial showed a greater percentage of
Crohn’s disease patients with draining stulae achieving stula closure by week 52
with vedolizumab compared to placebo [1]. There were similar ndings in the
ENTERPRISE study where >50% of patients with stulizing CD treated with
vedolizumab (with concurrent seton until week 14 and antibiotics until week 6) had
>50% decrease in the number of draining perianal stulae [2].
UST has been effective in Crohn’s patients including those patients who are
refractory to iniximab. While the data for use of UST for treating EIMs didn’t
show statistical signicance, UST is effective in treating psoriasis and psoriatic
arthritis. There are some data that suggest that UST can be effective in patients with
perianal disease in CD.Notably, iniximab is the most effective and most studied
drug for treatment of perianal disease in CD, but UST may be useful in CD patients
not responding to iniximab who have refractory perianal CD. Being a self-
administered injection is more convenient for patients.
As mentioned above, there is no head-to-head trial comparing ustekinumab and
risankizumab. However, the absolute remission rates in separate trials were higher
with risankizumab [3]. If we have the freedom of choosing between the two, we
would start with risankizumab since it appears to be more effective than UST.We
also have some clinical experience in using it in patients with TNF-resistant perianal
disease with very good response. The safety prole for UST and risankizumab is
comparable. They are both effective for perianal disease but not the rst choice.
However, if we have a patient with Crohn’s disease and EIM, we usually start
with an anti-TNF; if the patient fails the anti-TNF, then we would consider UST or
risankizumab.
If the patient was amenable to an anti-TNF, would you choose that over the
other 3 drugs previously mentioned? How do you decide?
Anti-TNFs are long established with good efcacy and known safety prole in
treating CD.Treatment with anti-TNF agents appears to be more effective when
given earlier in the course of disease; rates of response and remission are higher if
given within 2 years of onset of disease.
Anti-TNFs also target extraintestinal manifestations (EIMs) of CD and should be
considered in such patients. IFX is very effective in patients with perianal and stu-
lizing disease.
D. Stein and S. Faidhalla
https://t.me/medicina_free
213
In this young patient with mild-moderate disease, no EIM or perianal CD, and no
previous biologic exposure, all options are reasonable and should be discussed
in detail.
We recognize that choosing therapy in patients with Crohn’s disease can be com-
plicated. To shed some light on positioning therapy, a recent meta-analysis by Singh
etal. [4] assessed the comparable efcacy and safety of biologics in patients with
Crohn’s disease and this may be a guide.
This study highlighted that treatment with anti-TNFs: iniximab or adalimumab,
consistently ranked high for induction and maintenance of clinical remission. And
iniximab in combination with azathioprine was the highest ranked treatment for
induction of clinical remission and maintenance of long-term remission in biologic-
naive patients.
It is also important to remember that anti-TNFs still play a crucial role in the
treatment of patients with high-risk phenotypes such as stulizing, penetrating, and
stricturing disease and also TNF-sensitive extraintestinal manifestations.
IL-23 blockade might be the preferred mechanism of action in patients who have
been previously exposed to TNF antagonists. Overall data suggest that both
ustekinumab and risankizumab are effective after either primary or secondary loss
of response to other biologics. Risankizumab and ustekinumab also appear to be
more effective than vedolizumab in patients who have lost response or have intoler-
ance to anti-TNF therapy.
It is also crucial to keep in mind that when you are dealing with a primary non-
responder, the best strategy is to switch the class of drugs. In cases of secondary
non-response, you can still try another medication within the same class.
References
1. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, Lukas M, Fedorak
RN, Lee S, Bressler B, Fox I.Vedolizumab as induction and maintenance therapy for Crohn’s
disease. N Engl J Med. 2013;369(8):711–21.
2. Schwartz DA, Peyrin-Biroulet L, Lasch K, Adsul S, Danese S.Efcacy and safety of 2 vedoli-
zumab intravenous regimens for perianal stulizing Crohn’s disease: ENTERPRISE study.
Clin Gastroenterol Hepatol. 2022;20(5):1059–67.
3. Ferrante M, Panaccione R, Baert F, Bossuyt P, Colombel JF, Danese S, Dubinsky M,
Feagan BG, Hisamatsu T, Lim A, Lindsay JO. Risankizumab as maintenance therapy for
moderately to severely active Crohn’s disease: results from the multicentre, randomised,
double- blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial. Lancet.
2022;399(10340):2031–46.
4. Singh S, Murad MH, Fumery M, Sedano R, Jairath V, Panaccione R, Sandborn WJ, Ma
C. Comparative efcacy and safety of biologic therapies for moderate-to-severe Crohn’s
disease: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol.
2021;6(12):1002–14. https://doi.org/10.1016/S2468- 1253(21)00312- 5. Epub 2021 Oct 22.
PMID: 34688373; PMCID: PMC8933137.
35 Ustekinumab vs Risankizumab inCrohn’s
https://t.me/medicina_free
215© 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_36
Chapter 36
Use ofVedolizumab inUC
DanielStein andSalinaFaidhalla
A 67-year-old man who quit smoking 6 months earlier is diagnosed with new-onset
left-sided ulcerative colitis that is mild to moderate in severity. He is started on oral
and rectal mesalamine but does not respond. He continues to move his bowels 4–5
times a day with a small amount of blood mixed in his stool. He would like to try
vedolizumab as his next course of therapy.
Is vedolizumab a reasonable option? If so, would you start steroids as well?
In patients with mild-moderate left-sided UC with active disease despite being
on an adequate dose of oral and rectal mesalamine, we usually add budesonide 9mg
daily for 12 weeks for induction of remission. We prefer budesonide to prednisone
due to its lower systemic side effects. We would start budesonide prior to escalating
to biologics and assess response.
If the decision was made to proceed with VDZ, then we would start budesonide
that clinic visit while waiting for the rst infusion of VDZ.We would then continue
budesonide for 12 weeks and stop without tapering.
Do you check vedolizumab levels early on?
There is some evidence that higher VDZ levels are associated with higher clini-
cal response and mucosal healing especially in UC.In a recent systematic review
and meta-analysis by Singh et al. [1], they reported that in UC patients, median
vedolizumab trough concentrations were consistently higher in patients achieving
D. Stein (*)
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical
College of Wisconsin, Milwaukee, WI, USA
e-mail: dstein@mcw.edu
S. Faidhalla
Department of Medicine Division of Gastroenterology and Hepatology, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: sfaidhalla@mcw.edu
https://t.me/medicina_free
216
clinical remission or endoscopic remission. Based on their meta-analysis, they sug-
gested that vedolizumab trough concentration >20 μg/mL at week 6 and >12 μg/mL
during maintenance may be associated with better outcomes.
Some providers do proactively check VDZ levels but we don’t do this routinely.
We only do reactive drug monitoring in the case of primary non-responders or sec-
ondary loss of response. We don't think that there is enough evidence supporting
proactive monitoring of the VDZ levels. We know what to do with anti-TNF levels
but with vedolizumab you have completely different mechanisms of action. How
high a level do you need to saturate those receptors? We don’t know. We don't think
that we necessarily know the full signicance of our vedolizumab levels.
The patient is responding to combination budesonide and vedolizumab but when
you stop the budesonide after 8 weeks his disease starts to are. His vedolizumab
levels are adequate.
How would you manage this?
Usually, when drug levels are adequate, and the patient’s clinical response has
been steroid dependent, the best next step is to switch therapy. However, in the case
of VDZ it has been recognized that it can take longer to achieve the desired clinical
response (6–8 weeks in UC, 10–14 weeks in CD).
In this patient who has been on the medication for 8 weeks, we would discuss the
options of giving the drug more time and continuing budesonide vs switching to
another agent. If at 10–12 weeks the patient still has no response, then we should
switch to another agent.
Do you ever suggest to your patients who develop UC after quitting smoking
that they go back to smoking a cigarette or two a day?
We wouldn’t recommend that the risks of smoking outweigh the benets, espe-
cially since we have so many options for treatment.
Are patients who develop UC after quitting smoking more difcult to get
under control?
There are no data to suggest that.
If you decide to give vedolizumab more time to “kick-in” how much longer
would you continue budesonide?
Maybe 10–12 weeks if they are primary non-responders, if they have partial
response then up to 6 months. If there is no clinical response and active inamma-
tion is conrmed with fecal calprotectin and/or CRP, then switching therapy to
another agent is reasonable. If the patient is doing poorly, we would switch medica-
tion earlier.
The patient continues to show a lack of response to VDZ
What is your next choice for patients who choose vedolizumab but fail to
respond to it?
In this patient with mild-moderate left-sided UC who failed mesalamine and
VDZ, available options include anti-TNFs and UST.Ozanimod is another option for
UC patients who are anti-TNF naive.
In this case, since this patient is older and has mild-moderate UC with no EIM
we would probably start UST. Obviously, a discussion with the patient regarding
treatment options is essential in choosing the next drug.
D. Stein and S. Faidhalla
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217
Reference
1. Singh S, Dulai PS, Vande Casteele N, Battat R, Fumery M, Boland BS, Sandborn WJ.Systematic
review with meta-analysis: association between vedolizumab trough concentration and
clinical outcomes in patients with inammatory bowel diseases. Aliment Pharmacol Ther.
2019;50(8):848–57. https://doi.org/10.1111/apt.15484. Epub 2019 Sep 4. PMID: 31483522;
PMCID: PMC7083298
36 Use ofVedolizumab inUC
https://t.me/medicina_free
219© 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_37
Chapter 37
Functional Diarrhea inIBD
AmirPatel
A 32-year-old woman with a history of Crohn’s involving the terminal ileum and
right colon has been well controlled on Humira. She now comes in complaining of
frequent watery diarrhea and rectal urgency. Her exam, CRP, stool cultures, stool
calprotectin, and colonoscopy are within normal limits. Are there other tests you
would want to run?
It sounds like her Crohn’s is well controlled and the symptoms are either
functional or bile acid related. How do you manage those patients?
We see that a lot. Many of our patients with Crohn’s disease will have overlap-
ping irritable bowel syndrome, and if they have ileal disease, we also think about
bile acid diarrhea. In this particular patient, you would also like to know their under-
lying medical history, do they have a history of depression, anxiety?
But I probably would start them on cholestyramine rst, to treat bile acid diar-
rhea. And if that doesn’t help, I would wonder whether this could be irritable bowel
syndrome. That, to me, is a little bit more difcult to treat. But some studies in our
inammatory bowel disease literature show that patients may do well with a low
FODMAP diet.
The other thing you think about, if this patient has ever had any stricturing dis-
ease, is the possibility of small intestinal bacterial overgrowth. So, it would be fair
to try a course of antibiotics as well.
A. Patel (*)
Dept. of Medicine, Division of Gastroenterology and Hepatology, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: ampatel@mcw.edu
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220
When you use cholestyramine, do you tend to use it once a day or several
times a day?
I typically use it once a day, mostly in the morning. I think that’s when they get
the most benet from it. So, I start it in the morning with a low dose, and if they
notice some improvement, I’ll increase the dose incrementally, but I just give it once
in the morning.
A. Patel
https://t.me/medicina_free
221© 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_38
Chapter 38
When toPostpone Infusions
PoonamBeniwal-Patel
A 32-year-old man has UC well controlled on iniximab. He has a history of sinus
infections in the past and feels like he has one now. He is due for his infusion
tomorrow.
Would you postpone the infusion? In which situations do you feel it is neces-
sary to postpone an infusion and why?
In the setting of a mild infection where a patient has been afebrile for 48 h, the
infusion is given. If a patient is hospitalized with an infection, we will delay therapy
given that source control is needed.
But this raises an interesting question. It used to be that the only biologic agents
available were the anti-TNFs, and we would have to struggle with this dilemma. But
now, if I have a patient who keeps getting recurrent sinus infections, in the absence
of any anatomic defects, and we are really thinking that it’s the iniximab that is
increasing their risk of infections, I actually have changed them over to vedoli-
zumab if they’re in deep remission. It’s nice that now, we have other options, other
medications that may not increase the risk of things like sinus infections or
folliculitis.
What are some other examples of patients where you’ve told them it’s not a
good idea to go ahead with their infusions?
With COVID, if someone was diagnosed within the last couple of days, we'll
have them wait a week and make sure they haven’t spiked a fever for a few days
before administering an infusion. But outside of having a fever or a prolonged infec-
tion where source control with antibiotics hasn’t been achieved there really are very
few scenarios where we will postpone an infusion.
P. Beniwal-Patel (*)
Medicine, Gastroenterology/Hepatology Division, Medical College of Wisconsin,
Milwaukee, WI, USA
e-mail: pbeniwal@mcw.edu
https://t.me/medicina_free
223© 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_39
Chapter 39
Musculoskeletal Complaints inaPatient
onAnti-TNFs
AmirPatel
A 35-year-old woman has been receiving iniximab for 2 years for Crohn’s disease.
Her ileocolitis has been under good control, but she comes in complaining of joint
pain in her knees and ngers which is something new for her. On exam, her joints
seem tender but not acutely inamed.
When do you consider the possibility that a patient with IBD who develops
new musculoskeletal symptoms might be experiencing an adverse reaction
from their anti-TNF?
Arthropathy is common in inammatory bowel disease. There are two types.
Type one is generally peripheral, acute, and involves less than six joints. That type
of arthropathy typically occurs at the beginning of the disease. It’s self-limiting,
non-erosive, and correlates with ares. So, if someone has active colitis, they typi-
cally complain of joint pains, commonly affecting the knees and elbows in my expe-
rience. Type two is more polyarticular. The MCPs, the small joints, are commonly
involved. These do have active synovitis but this type of joint pain does not correlate
with IBD ares and can happen years after the disease commences. That’s one thing
I think about, but if someone’s been on an anti-TNF for a couple of years and now,
they start having arthralgias, I do start wondering if this could be a side effect of the
Remicade.
Usually, I see arthralgias as an adverse reaction to Remicade occurring early
after initiation of therapy. If it starts up years later, then I do get concerned about
conditions like drug-induced lupus, where I consider referring the patient to the
rheumatologist.
A. Patel (*)
Dept. of Medicine, Division of Gastroenterology and Hepatology, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: ampatel@mcw.edu
https://t.me/medicina_free
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