Dr GI Joe

Welcome back to the Deep Dive.

So today we're tackling something I know a lot of you are navigating.

The really complex flow chart, you could say, of modern Crohn's disease treatment.

That' right.

We're going to beyond just listing the drug type.

Exactly.

We want to get into the nitty gritty, the actual evidence-based sequencing.

How do clinicians choose?

And when do they switch, Especially looking at, you know, luminal versus fistralizing disease, big difference there.

Huge difference.

And it really boils down to a core strategy, while two fundamental pillars that guide almost everything now.

Okay, let's lay those out .

Pillar one, I think we can all agree, avoid long-term steroids at all costs.

Absolutely.

There' a bridge, maybe, but never the destination.

We know the damage they can do long term.

Right.

And pillar two, the treats to target approach.

TTT.one hears it, but what does hitting that target actually mean objectively?

What are we looking for in those first, say, 12 to 16 weeks?

Yeah, those checkpoints are critical.

We're not not just going by symptoms, which can be misleading.

We need objective proof the inflammation is down.

So what are the numbers?

Specifically, we're aiming for a fecal cow protect or FC level. Idedeally, less than, or equal to 250 micrograms per gram.

Okay, FC other 250.

And a C reactive protein, CRP, down to 5 milligrams per liter or less.

These tell us about gammation and systemicamm.

Got it.

Less than 250 for FC, less than five for CRP .

And if you don't hit those early on..

And the strategy pivots, you have to escalate.

It changes the whole pathway.

Okay, let's start as square one, then.

Mild, uncomplicated crrohn.

Just in the terminal helium, maybe the right colon, no nasty stuff like abscesses or strictures yet.

What's the first move?

This is where the Boot and Iide Bridge comes in.

We're talking about the controlled IO release form, CIR Boots andide, usually nine milligrams a day, orally for about eight weeks or so.

And the idea is it releases right where you need it.

Exactly.

Right there in the distalelium and maybe the start of the colin.

So you get the anti-inflammatory effect without, hopefully the major systemic steroid side effects you'd get from something like prednisone.

But you mentioned it's a bridge, so the key rule here is...

Induction only .

Never, ever for maintenance therapy.

It doesn't provide that deep, long-term healing needed for T2T. It just, you know, calms things down short term while you see if it's enough or if you need more firepower.

Good clarification.

Yeah.

Now, I noticed the source is really worn against some common, maybe older practices for this kind of mild, small bones .

What should clinicians not be reaching for?

Right.

Definitely avoid the five ASA drugs, malamine, things like that.

Oal or rectal, they just don't really work well for controlling inflammation in the small bowel.

Okay, so five ASAs are out for small bowel diseasease.

Yeah.

What about antibiotics?

Cypro, Metronidisol?

Also, not for routine luminal inflammation .

They have their place, absolutely, for infections, maybe short term adjunct and falizing diseases, which we'll get to, but not for just treating the underlying Chn's inflammation itself.

Okay, so let's say we try the Boots and I Bridge.

Eight weeks go by, and those targets, the CRP under five, the cow protected under 250.

They're not met.

Or maybe the patient feels better, but flares right back up when they stop.

That's the pivot point right there.

That failure, whether it's non-response, partial response, or flaring right after stopping, defines steroid refractory or steroid dependent disease.

And that's the trigger.

That's the trigger.

It doesn't matter if symptoms feel mild right now .

Objectively, the disease isn't controlled by first line induction.

You must escalate to advanced therapy, biologics or small molecules.

Okay, so steroid failure kicks you up a level, and we should probably just quickly define severity again.

It's not just symptoms..

Not at all.

It's symptoms, biomarkers, and complications .

And the key thing to stress, like you said earlier, is, any complication, a fistula, a stricture, automatically pushes the disease into the functionally severe, category, even if the patient feels okay day to day.

Makes sense.

So we've escalated.

We need an advanced therapy.

Let's say it's luminal disease, moderate to severe, or steroid refractory.

Biologic naive patient.

What are the top two contenders for first line treatment?

This is often framed as a choice between maybe depth of evidence versus simplicity.

You've got inflixM, the N anti-TNF workhorse.

The veteran.

The veteran, exactly.

Decades of data, highest proven rates of deepal healing, and the huge advantage of therapeutic drug monitoring TDM.

You can measure levels, adjustsing precisely.

Sounds great.

What's the catch?

What are the considerations?

Well, to get the best long term results, you often need comotherrapy, adding something like low dose as a theoprane or methotrexate to stop the body making antibodies against the inflomab.

And historically, it meant 4V infusions.

Ah, the infusion center overhead.

Right.

And there's that specific safety flag .

Avoid antit.Fs, all of them, really, in moderate to severe heart failure, NYHA 3 or 4, trial data showed potential harm there.

But you mentioned historically infusions.

There's a change there for inflict ab maintenanceance now, isn't there?

The subcutaneous option?

Yes, that's a big deal for patient convenience.

Zra.

After the IV induction doses, you can switch to a subcutaneous shot 120 milligrams every two weeks.

It gives you much less disruption.

Okay, so inflict with TDM and out SE maintenance.

What's the other main first line option, the simplicity choice?

That would be resizume, an IL 23 inhibitor.

It's become a very common, arguably, the default first choice for many now.

Why the default?

Strong data, particularly on end endoscopic healing.

It works really well as monotherapy.

You generally don't need that second ammunosuppressant drug.

And the maintenance is just a subcutaneous injection every eight weeks.

Eight weeks.

Wow.

And TDM.

Not routinely needed.

It has very low immunogenicity, meaning the body is much less likely to form antibodies against it, so simpler monitoring, easier dosing schedule.

Okay, inflix a map versus reses's map, but there's another player that seems really potent , Yupidib, the oral JAK1 inhibitor.

Sources say it's highly effective, maybe be the fastest acting.

It is very effective, and yes, incredibly fast online.set, noticeable improvement often within days or weeks.

And being a pill is a huge plus for many patients.

So fast, oral effective.

Why isn't that the automatic first choice then?

It comes down to the safety profile, specifically the class wide boxed warnings on JKhibitors.

These warnings cover risks like major adverse cardiovascular events, MAE, blood clots, or VTE, malignancy, and even death.

Right, the boxed warning looms large , Even if the actual risk in a younger Cone's patient without heart issues might be pretty low.

Exactly.

The warning stem largely from studies in older rheumatoid arthritis patients who already had cardiovascular risk factors, the warning applies across the board, regardless of age indication.

So caution is the word.

Where doesidib UPA fit in them?

It's generally reserved for those st refractory or dependent cases, or after a first biologic has failed, especially if speed is really needed, or the patient strongly prefers an oral route, but you have to weigh those risks carefully.

And there's monitoring involved, too, right?

Yes .

Baseline and ongoing checks for blood counts, liver, function, liids.

And crucially, the patient needs to be vaccinated against shingles, before.

Okay., let's map out the failure sequence for luminal disease.

Say you start with an anti-TNF, like inflicts a , and it fails, either loses response or never works well enough, what's the standard next move?

You generally want to switch to a different mechism of action, so the best evidence and most common next step would be Rizum, thehibitor.

Strong monotherapy.

Alternatives, if Riz isn't suitable for some reason.

Suustinab, which hits both aisle 12 and ale 23, is another solid choice .

Or, again, if speed is paramount and the wrist profile fits, Oadacetib is an optionion there.

Now slip it.

What if you start with Rozaki Zumab, the IL 23, and that fails?

Then you'd likely pivot back towards an anti-TNF, probably in Flixumab, specifically to leverage that TDM capability.

You can really fine-tune the dosing to overcome whatever caused the failure.

And UPA is an alternate again?

Yes.

Uidas Tib remains an option there, too, particularly for that rapid oral benefit, if needed.

Okay, one more drug in the aluminal mix.

Vitalizumab.

The Gut selective Integrin blocker.

Where does it fit?

It sounds super safe.

It is the safest, generally speaking.

Very low risk of systemic infections because it works primarily in the gut.

That's its major advantage.

But it tends to be slower acting compared to anti-TNFs or UPA, and the data suggests that might might be slightly less effective, especially for disease predominantly in the oium.

So it's often not the first choice for moderate to severe aluminal disease.s more of a fallback?

Often, yes.

Or a first choice if safety is the absolute top priority, maybe an older patient, or someone with high infection risk.

But for pure efficacy, especially in the alien,ixomab and reasonizab are usually.

Right.

That clarifies the aluminal side.

Now, let's shift gears completely .

Fizing disease. Penetrating complications, pal fistas internal fulas.

You said this changes everything.

Everything.

The priority shift immediately.

It's not just about calming gut lining inflammation anymore.

Now you have infection, tunneling, potential abscesses.

So before you even think about maximizing the advanced drug therapy, what's the absolute non-negotiable first step?

Source control.

Always, always source control first.

If there's an abscess, it must be drained.

Fis tracks often needons, place those little drainage tubes, usually done under anesthesia and EUA.

You can't just throw a biologic at an active abscess or an undrained fula.

You really shouldn't.

It won't work well, and you risk making things worse .

You need to drain the infection, establish drain drainage pathways withetons, then you bring in the heavy hitting medical therapy to heal the underlying inflammation driving the fistula.

Okay, source control first.

What about antibiotics here?

Cypro, Flagile?

They have a role, but it's usually short term, often used as an adjunct while biologic starting at work, just to help control the bacterial load.

They are not a long-term solution for fially healing on their own.

Got it.

So source control done, maybe short term antibiotics.

What's the go-to medical therapy the first biologic for active period?

Here, the anti-TNF still reigns supreme, specifically in flixomab.

It has the best, most robust evidence for fistula healing, going back to trials like Ex 2.

What kind of success rates are we talking about?

The Ex2 data showed fistula closure rates around 36% at one year with inflictimab maintenance.

Adal, another antiNF, is generally considered the next best option in this class.

Now, you mentioned TDM for inflixMab earlier.

Is it different when treating fistillas compared to just luminal disease?

Yes, critically different.

This is a key point.

For fiscial healing, we aim for significantly high inflixomap trough levels.

Higher levels.

Why?

The data strongly suggests that you need more drug exposure, higher concentrations systemically, to penetrate those inflamed f tracks and promote healaling often targeting troughs above , maybe even above 15 micros per mill, much higher than the typical target for just mucosal healing.

Wow, okay.

So higher targets for fistulas with anti-TNFTDM.

Now, the big divergence.

If anti-TNF fails to heal the fistula, what's next?

You don't just jump to Ranis Mob likeuminal failure, right?

Correct.

This is where the pathways really split.

While Rizum is great for the luminal surface, we just don't have strong specific data showing it works well for fish as yet.

So if anti-ina fails fula, where do you go?

The best evidence currently points towardustkab.

That's the ale 12 and ale 23 blocker.

It has the most compelling data among the non-NF options after anti-TNF failure for falizing disease.

What kind of results disease to Kenny Mab show in that setting?

Real world studies suggest clinical remission or significant improvement in fistulas in maybe the 40, 45% range after antiNF failure.

So it's a solid second line choice here.

Okay, so let's recap that sequence clearly for the listener, Luminal Failure.

Anti-TNF likely goes to recent Kizab, IL23, Fistula failure.

Anti-TNF likely goes to resumab, IL1223.

That's the core logic based on current evidence.

And after Uukkinomab for Fulas, what are the subsequent options if that doesn't work?

Then you might consider Uppadasa Tinib, the JAKhibitor, again, weighing the speed and efficacyfficacy against the safety profile.

Vizab could be an option, but understanding it's likely slower and less effective for F's closure rates may be around 20 .

So it's often a later choice driven more by safety needs.

This is really highlighting how phenotype drives the sequencing.

Okay, zooming out a bit, let's touch on some key contraindications or special populations.

When do you absolutely avoid anti-TNFs?

Two main situations. Moderate to severe heart failure, like we mentioned, NYHA 3 or 4.

And any history of deminating disease, like multiple sclerosis, in those cases, you'd prefer an IL2, like Rankum or in V .

Okay.

And conversely, when do you have to be most cautious or avoid the JA inhibitors, like Oib?

Primarily, in patients with high cardiovascular risk, older age, history of heart attacks, stroke, or blood clots.

BTE.

That boxed warning makes us very cautious there.

Again, you'd lean towards the biolog with cardiovascular safety.le 23'sab.

What about preancy planning?

Any specific considerations there?

Yes.

Certab Pgel, which is an anti TNF, is often preferred if anti TNF is needed during pregnancy planning or pregnancy itself.

It's engineered differently, lacking an FC region, which means very little of it crosses the placenta compared to other antiN.

NJA inhibitors in pregnancy.

Generalally avoided, not recommended during pregnancy conception planning due to lack of safety data and potential risks.

We sometimes hear about another drug, not Lisa's.

Why isn't that used more often in chrome's?

Nusab is very effective, but it carries a significant risk of a rare but devastating brain infection called progressive, multifocalucocephalopathy, PM, especially in patients positive for the JC virus.

Wow, the PML risk.

Exactly.

It requires a very strict monitoring program called touch rims, with safer effective options like Volusum available, which is also gut selective, but without the PM risk, is really reserved for very specific, highly refractory cases , almost as a last resort.

Makes sense.

And just to quickly circle back on TDM, therapeutic drug monitoring, we know it's key for inflixM, especially for fistas, which other advanced therapies routinely use TDM.

It's really most established and useful for the anti-TNF's inflixab and a dilema. .

They have known issues with amicity and a cleare link between drug levels and response.

And not for the others.

Generally not standard practice for the Isisle 23 inhibitors, like Rizab orustinab or the JK inhibitors like Yupetib, they tend to have less immunogenicity or different mechanisms where trough levels aren't as clearly predictive or actionable in the same way.

Wow.

Okay, this deep dive really makes it clear.

Choosing an advanced therapy for Crohn's is absolutely not random .

It's a highly calculated decision.

It really is.

Based on phenotypeuminal or fistializing, based on the desired therapeutic leverage, do you need TDM control?

Speed,otherapy convenience, and always layered with patient specific safety and risk escapeessment.

You're constantly weighing the power of the drug against the potential risks it introduces for that specific patient.

Precisely.

Which brings us back to that tension we touched on earlier, especially around the J.

Gay inhibitor box warning .

You know, that warning came largely from studies in older RA patients, often over 50, with existing cardiovascular risks.

That's right.

That was the population where the signal emerged.

But the regulators applied that that warning across the board.

So here's the provocative thought, maybe, for our listeners to mull over.

Good on.

For a young Chn's patient, say in their 20s or 30s, otherwise healthy, low cardiovascular, risk , who might really benefit from the speed and oral convenience ofididb to get rapid control and heal.

Are we always making the best choice for their long long-term outcome by strictly adhering to a warning derived from a very different, much higher risk population?

That is the exact clinical dilemma we grapple with.

How do you balance a broad regulatory warning designed for maximum population safety with the nuanced individualized risk benefit assessment needed for the patient sitting right in front of you?

It really highlights that ongoing tension between label constraints and personalized medicine in the real world .

Definitely something to keep thinking about as these therapies continue to evolve.

Thank you so much for walking us through this complex landscape today.

My pleasure.

It's a critical topic.

Absolutely.

We'll see you next time for the Deep Dive.