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I'm Dr. Joseph Kumka, Gastroenterology Fellow, educator, and creator of this podcasts. Whether you're a resident gearing up for the boards, a fellow diving deep into subspecialty topics, or a practicing clinician hungry for high-yield updates—you’re in the right place.
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Welcome back to the Deep Dive.
Today, we're tackling the really complex world of managing all sort of colitis.
You, the listener, you know, the field's just exploded recently biologically, small molecules.
It feels less like a clear path and maybe more like the Wild West sometimes.
Oh, absolutely.
It's true.
There are so many effective options now, it can be well, overwhelming.
And that makes the strategy how you sequence these drug, the whole failure matrix, so incredibly important.
Our mission today, really, is to give you a clear map.
You know, what drug to start?
When do you say, okay, this isn't working?
And then the crucial rules for switching to the next thing without losing valuable time?
Right.
We need that structure.
And presumably, that structure has to be based on objective measures, not just how someone feels day to day.
So where do we start building this protocol?
The cornerstone is definitely the treat to target approach.
It's become standard, really.
We're not just aiming for symptoms to get better.
We want objective, measurable healing inside the cold. Colon.
So, we track three main things.
First, the short term clinical response, obviously , then intermediate biomarkers, and finally, the big one, long term and descopic healing.
Okay, tell us more about those intermediate biomarkers.
They sound like they're the key, maybe to deciding failure around that 8 to 12 week mark.
They absolutely are.
They're critical checkpoints.
We need CRP, C reactive protein to normalize, get back into the normal range , and probably even more importantly, fecalal protectin, or FC.
We need to see that trending down significantly.
FC gives us a really good picture of the inflammation actually in the gut.
We're aiming for a target somewhere around 100 to 250 micrograms per gram, maybe even less .
If those numbers, the CRP and XC, aren't really moving in the right direction by 8, maybe 12 weeks, well, then the current treatment step has likely failed.
And the ultimate goal, the sort of a gold standard finish line.
That would be endoscopic healing.
We want to see it on camera.
Specifically, that means getting the Mayo endoscopic subscore, the M , down to one or even the zero.
That signifies real mucosal healing.
Okay, got it.
Let's start with the mild end of UC then.
The first principle seems pretty elegant here.
Deliver the drug right to the disease.
So that means five ASA agents , specifically mezzoline.
But how you deliver it seems critical.
It really is.
Location, location, location, you could say.
If the disease is just in the rectum that's ulcerative proctitis, maybe the first 18 centimeters or so, then topical delivery is definitely best.
A one gram may solidomine supposit usually taken nightly , and it's used for both getting things under control, induction, and for keeping them that way, maintenance.
That's generally preferred over rectal steroids because you get that long term maintenance benefit with the missile.omy.
Makes sense.
What if the inflammation goes further up, say, into the left side of the colon?
Okay, once you're dealing with left-sided colitis, combination therapy is really the way to go.
This is a key point .
You need oral malamine, usually two to three grams a day, you need rectal malamine enema, at least one a day.
The guidelines are quite clear on recommending that combination.
Why?
Because the enema insures good coverage of the distal colon, which the oral drug might not reaches effectively.
Right. Covering all the bases.
Yeah.
But for extensive colitis, where the inflammation is, you know, past the splenic flexure, we're then relying just on oral drugs .
Given that getting people to take meds every day can be tough, are we maybe sacrificing some effectiveness there for convenience?
That's a really practical, important question.
Compliance is always a factor.
Fortunately, for extensive disease, oral molamine, at a dose of at least two grams per day is effective .
And importantly, studies have shown that once daily dosing is generally acceptable, that definitely helps people stick with the treatment plan.
So let's say we've optimized the 5 ASA, maybe using combination therapy if needed, and we wait eight weeks, 10 weeks, 12 weeks.
But the biomarkers, FC, and CRP, they're still high, or the patient's still having significant symptoms?
What's the very next step ?
And how do we define failure clearly before jumping to, well, the bigger guns?
Okay, if that optimized 5A approach isn't cutting it, the immediate bridge is typically adding oralide MMX.
That's nine milligrams, once daily.
But here's the really crucial part.
Boot MMX is a type of steroid, a controlled release one, and it absolutely must be used strictly for induction only, just to get things cooled down.
Right.
It's just a temporary fix, not a long-term solution.
So failure here really means you can't get them off the steroid without the disease coming right back.
Exactly.
That's the core definition .
Failure means either no real clinical or biomarker improvement by that 812 week mark.
Or maybe more commonly, the patient feels better on the boots and MMX, but every time you try to taper them off, they immediately flare up again.
That inability to maintain remission without steroids is the trigger.
It pushes you definitively into the moderate to severe pathway and the need for advanced therapies.
Okay, so we fill the foundational 5ASA, maybe even the Bootside Bridge.
Now we hit that big fork in the road for moderate to severe out.patients.
Inixomab, IFX , versus vetitalism BDZ as the first advanced therapy.
I feel like the recommendations on this keep shifting.
If IFX works faster and lets us use TDM, you, therapeutic drug monitoring, why do guidelines often lean towards vitalism first?
Yeah, that's probably the central trade-off.
We're constantly weighing in, you see RawBeed and maybe initial power versus long-term safety .
The ration for defaul to, let's call it, our default anchor is really about its mechanism.
VDZ is an integ inhibitor.
It works specifically in the gut.
So fundamentally, it has a better overall long term safety profile, less risk of systemic immunosuppression, fewer systemic infections.
And this is heavily influenced by the varsity trial, I assume.
Precisely.
Varsity was a a head to head trial comparing VDZ to Adalomumab, which is another anti-NF, like inflixomab .
And it showed VDZ was better for achieving remission at one year, and importantly, it led to fewer systemic infections.
So it's seen as the safer, gut selective choice for the typical biologic na outpat.
Okay, so when do we choose inflixab then, our anchor too?
You lean towards inflixomab, IFX, when when the patient presents with a really high inflammatory burden.
Thinks severe symptoms, very high CRP , maybe deep ulcers seen on their scope, or simply when you need the absolute fastest possible induction.
IFX being an anti-NF is generally considered the most potent and fastest acting of the classic biologics.
And you're right, the ability to use TDM early on checking drug levels and antibodies is a big advantage with IF .
It lets you optimize the dose quickly if needed, which is really valuable when you're dealing with aggressive disease.
Okay.
So whether we start with VDZ for safety or IFX for speed, let's say the drug fails..
Again, around that 812 week mark, what's the absolute number one rule for the next move?
The cardinal rule is switch mechanism do not cycle within the same drug class for primary non-response or loss. Response.
So if you failed IF, an anti-NF, you don't just switch to another anti-NF, like a Dalma map, you need to move to a completely different pathway.
Same thing if you failed BDZ, the integrin inhibitor, you have to pivot to a different mechanism of action.
Right.
So that leads us to the main second line choices.
Yeah.
The JAK Inhibitors and the IL 23 inhibitors.
How do we choose between those?
It comes back to that same sort of trade-off-off.
Speed versus safety revisited.
If speed is still the primary driver, maybe the patient is quite unwell , you'd likely go at the JKhibitor like Gupa Detib or to a faucetib.adetib, in particular, consistently ranks very high in network meta analyses, those big studies comparing multiple drugs.
It ranks high for both induction and maintenance efficacy, largely because it works so quickly.
But the JKs come with some baggage, don't they?
Those black box warnings are significant.
Yes, they absolutely are.
It's important.
JK inhibitors are oral small molecules, but they're not gut selective.
They work systemically.
And they carry those boxed warnings regarding increased risks of things like major adverse cardiac events, MCE, blood clots, VTE, and infections like shingles or exha .
So you absolutely must screen patients carefully for these risks before starting a Jhibitor.
Okay.
So if those risks seem too high for a particular patient, or perhaps of long-term safety and durability, are more the priority, then we'd switch to theis 23 inhibitors instead.
Correct.
That's the alternative pathway.
Drugs like Marykisima, Brazenkisima, Balab, they target the aisle 23 pathway, which is higher up in the inflammatory cascade .
They offer very good efficacy, but generally with a more favorable and durable safety profile compared to the JK inhibitorser systemic concerns.
And just as a practical point, Pukab currently has the advantage of offering a fully subcutaneous induction regimen, which some patients prefer over 5 E infusions.
Interesting.
And there's also this other category, this sort of oral non-JK.
Lane.
Yeah.
The S1P modulators is a trodin those, a different pathway entirely, right?
Where do they fit into this sequence?
Yeah, they work on S1P receptors.
It's another distinct mechanism.
They are really important alternatives.
They can be a good first option for patients who strongly prefer oral therapy but want to avid or perhaps can't take a JKhibit due to those boxed warnings .
They can also be used later, maybe second or third line after failing other mechanisms.
They aren't without their own checks, though.
They require specific cardiac and ice screening.
This whole discussion seems underpinned by this metric I keep seeing in studies SUCA.
Surface under the culative ranking curve.
That sounds complicated.
Can you sort of quickly demystify SUCRA for us?
It seems key to understanding why VDZ might be first line, despite Yadastatinib. , often ranking highest on efficacy.
Right.
SUCA sounds technical, but the concept is fairly straightforward.
So Basically, a statistical method used in these network meta analyses, or NMAs to rank all the different drugs against each other based on their overall performance across multiple studies.
If a drug has a high SCCRA score for say, efficacy , it means it consistently performed better than other drugs in achieving that outcome across the data.
The key takeaway and what SUCR helps quantify is exactly what you said.
Eup often gets the highest SUCRA score for pure efficacy and speed of onset .
But Vel tends to rank best when the analysis focuses on safety, specifically looking at the lowest rates of adverse events or serious infections.
So the SUCA scores just provide the statistical backupup for that core clinical decision you're always making, balancing that raw efficacy against the long term safeness of file.
Okay, let's shift gears dramatically now.
The hospital setting, the real crisis. Acute, severe ucerative colitis, or ASEC.
This is the inpatient emergency pathway.
What needs to happen the moment that patient hits the door?
Yeah, this is high stakes.
Admission is the first step, obviously .
Then immediately start high dose IV steroids, typically IV methylredness alone, around 60 milligrams a day for about three to five days.
You also absolutely need DVT propyllaxis, blood clot prevention, and crucially get an early flexibility sigmidoscopy.
You need that scope to confirm the diagnosis, assess the severity, and importantly rule out other things like CMB colitis, which can mimic fla .
And here's a really important clinical pl foratients.
Do not continue add medications while the patient is receiving high do IVeroids for AS doesn't help and even cause.
Got it.
No 5 ASA and ASC.
The clock is ticking very fast here.
The first major decision point comes at day three, It does.
Day three is critical.
We use the Oxgen criteria.
It's a simple scoring system looking at stool frequency and the CRP level.
This helps predict fairly accurately, which patients are likely responding adequately to the Ivy steroids.
If they meet those criteria for non-response, you can't wait around.
They need to move immediately to a rescue therapy.
And the main rescue options are IV Inflixomab or IV Cycorine, CSA.
Is it basically a coin toss or are there clear reasons to pick one over the other?
Well, both actually offer similar sh short-term effectiveness in preventing collectomy, so it's not quite a coin toss.
The choice is more strategic, often based on the long-term plan.
You' generally favor inflictab, IFX, if you want a smooth transition to maintenance thererapy.
If the patient responds to the IFX rescue, you can just continue with standard IFX maintenance dosing long term, easy transition.
Also, some data suggests IFX might be preferred if the patient's album and level is very low, say, less than 2.5 GDL, though that's debated.
Okay.
And when would you opt for cycosp brain?
It seems more complex, requires that careful trough monitoring.
You'd strongly consider cyclist, CSA.
If the patient has had recent or ongoing exposure to an antiNixomab, you need a different mechanism quickly in that scenario .
Or you might choose CSA if you're specifically planning a bridge strategy, meaning, use CSA just for the acute induction phase to get them out of the hospital crisis and then plan to transition them fairly quickly to a different maintenance therapy, like a village.omab or maybe athopurian, because CSA isn't suitable for long term maintenance .
And yes, it definitely requires close monitoring of drug levels. Troughs usually 15250 in GML, and watching carefully for potential kidney or neurological side effects.
Let's just pause and confirm a really critical point here.
This could be lifaving.
Is cyclosreen ever used as rescue therapy for a severe Crohn's disease fla?
Abssolutely not.
That's a crucial distinction.
Cyclosp is specific to acute severe ulative colitis ASD .
When dealing with a severe Crohn's flare requiring hospitalization, the immediate focus is different.
It's heavily geared towards ruling out surgical problems, things like abscesses or bowel obstructions.
If it's confirmed to be purely inflammation, driving the severe Crohn's flare, then inflict aab is generally the standard medical rescue therapy.
Keep those two pathways, UC rescue and Cronhn's rescue completely separate in your mind.
Okay, crystal clear.
So back to ASC.
If the chosen rescue therapy, whether it was IFX or CSA , isn't working by day five to day seven, what then?
At that point, you've really reached the end of the line for medical management in the acute setting.
If there's no significant improvement by day five to rescue therapy, then an urgent surgical consultation for me planning is necessary.
All right, let's try and synthesize this now for the long haul, the maintenance phase.
We touched on TDM for inflixamab earlier .
How does therapeutic drug monitoring specifically guide the next step if IFX seems to be failing?
Yeah, TDM is incredibly useful, almost essential, when managing potential IFX failure.
It helps you understand why it might be failing.
It's quite logical.
If you check levels and find the drug level is low, but there are no significant antibodies against the drug, then the answer is usually simple, dose escalates. Increase the dose or shorten the interval .
But if the drug level is actually adequate, or if there are high levels of antibodies neutralizing the drug, then just increasing the dose won't help.
That tells you the mechanism itself isn't working for that patient anymore.
And in that case, you absolutely must switch to a different mechanism of action.
Okay, perfect.
So can you lay out the definitive if this fails, then do that sequenc ladder again?
Let's start with that average biologic, naive patient where we're maybe prioritizing safety first.
Sure.
Following that safety first guideline supported approach, the typical ladder looks something like this.
Step one.
Start with Villyoomab, VDZ.
That's the gut selective safety focused anger.
Step two.
If VDZ fails, you must pivot to a new mechan.
The main choices are either aKhibit, like, or an 23 inhibit, like Mirizum orizum .
The choice there depends on the patient and priorities at that moment.
Step three, Whichever mechanism you didn't choose in step two, you generally try that next.
So if you went JK first, you try ale 23 next, or vice versa.
Step four, after exhausting those, you'd then look towards theatasm , or perhaps circle back to the anchor you skipped initially, like try and infl some if you started with VDZ.
Step five.
And finally, you have options like usinab, which targets aisle 12 and ale 23 or other remaining therapies before surgery becomes the primary consideration.
And the fundental principle we through all of that.
Switch mechanisms.
If you experienced primary non-response or secondary loss of response to a drug, whether it was an anti-N, an integ inhibitor, JK, whatever the next step is almost always to switch to a different class , don't waste time cyc within the class, like trying another anti-TNF after the first one failed, unless TDM specifically points to inadequate drug levels as the reason for failure.
And one last point on monitoring.
Even if the patient feels great and their biomarkers like FC and CRP look perfect at, say, three months after starting a new therapy, we still generally need that objective check.
We typically we about six to 12 months after induction to do a follow-up colonoscopy to confirmucosal healing, aiming for that one or zero.
Wow.
Okay, this deep dive really hammers home that managing UC effectively isn't about finding one single best drug for everyone.
It's much more about carefully choosing the right drug for the right patient at the right time, constantly balancing that risk profile safety versus speed, and then being really decisive and object objective on the biomarkers tell you it's time to switch.
We're navigating maybe five distinct drug classes here.
The therapeutic armamentarium is truly remarkable now.
The ability to rotate through these different mechanisms, integr inhibitors, anti-TNFs, J 'sisle 23 is SPs gives us so many shots on goal before we have to consider surgery.
It's a huge advance.
So here's a final thought for you, our listeners, to consider.
We heard how the hard data, the SUCRA analyses, often show JAK inhibitors like Yadasi Tib, offering the best raw efficacy and the fastest results.
But we also heard about the superior long-term gut selective safety profile of drugs like they'llose a .
So looking ahead, maybe five years from now, what do you think will truly determine the default first line advanced therapy choice?
Will it be those powerful, maybe undiable efficacy and speed scores?
Or will the long term safety advantages of the gut selective drugs keep them anchored as the go-to starting point?
You now have the framework, the targets and the sequencing rules to really track how this fascinating field continues to evolve.