Treatment principles in Crohn's disease: a graphical thread 🧵 (n~28)

There is lots covered here
• impact of CD
• early effective therapy
• surgical trends
• biosimilars
• head to head studies
• mucosal healing

Follow along below👇
Crohn's disease can have a significant impact on a person's life:

• physical aspects
• psychological aspects
• long-term complications of disease (and therapy)
• everyday life

We should remember this as physicians when we talk to our patients in clinic
This thread is based on a lecture I gave to the 1st annual BRICS IBD Symposium (Brazil - Russia - India - China - South Africa) last weekend

I recorded the talk which you can watch here
Unfortunately treatment failure and disease progression are common in Crohn's disease

• many patients have had Crohn's disease for a long time
• we have not always had effective therapies
• nor have we known to use therapies effectively until now
We are now in the multi-drug era for treating both Crohn's disease and UC

This is really the biosimilar anti-TNF era
This is the time when anti-TNF therapy should be affordable to all
And should not cost more than 2000 GBP per year

That changes everything
We know that Crohn's disease is progressive

Early in the disease course inflammation predominates

This is why early effective therapy works

The data from the anti-TNF studies shows this very clearly
This recent brilliant analysis by @ShomronH (individual patient level meta-analysis of RCTs) clearly shows the effect:

• in Crohn's disease the biggest benefit from biologics comes with a shorter disease duration
• BUT we do not see this effect in UC…
Our data in Edinburgh by @PhilWJenkinson show the change in biologic prescribing over the last 20 years

Note how the shape of the curve changes in the right hand panel - in recent years more top down therapy

This is associated with fewer surgeries…
We have been early adopters of biosimilars in the UK and especially in Edinburgh

This has facilitated big cost savings for the health service

We have re-invested this into our service

It has allowed us to use effective therapy early

And get access to newer therapies
You can see how our use of adalimumab has increased over time

This is almost all Crohn's disease (we use very little ADA in UC)

The rise in ADA prescribing anticipated the switch to biosimilar in 2018/9

@LauranneDerikx published our data…
This is the most important chart

• at diagnosis we need to predict risk of complicated disease
• we need to stratify therapy according to predicted response

However, we cannot yet do this ... therefore we must use a treat-to-target approach to monitor and adjust accordingly
Treat-to-target per STRIDE-2

The framework is simple
• set a target btwn physician & patient
• control symptoms; achieve mucosal healing; normalise QoL
• treat & monitor (CRP, FCAL + colonoscopy + MRI)
• if target not reached adjust therapy & proceed…
Precision medicine may not have given us all the answers to predicting risk in Crohn's disease

But we are not completely blind

The criteria listed here have stood the test of time

E.g. always start biologics at diagnosis with fistulas & extensive disease & deep ulcers
How to decide who gets biologics in Crohn's disease?

Start at diagnosis (within 3m) with fistulas & extensive disease & deep ulcers & other risk factors

And start early (1st year) if FCAL does not normalise (<250mcg/g)

By @plevrisn…
In the multi-drug era of IBD we have multiple effective therapies

How then to choose the right drug for the right patient at the right time?

This is often guided by cost
• Start biosimilar anti-TNF early in those where suitable
• For those where it is not use VEDO or USTE
Anti-TNF therapy is cheap and highly effective in Crohn's disease

Safety profile is well understood

BUT there is a problem
• 20% will not respond
• many will lose response

After anti-TNF failure other drugs work less well
Head to head studies have been highly informative in IBD over the years

The misconception is that these are new - let's revisit this for Crohn's disease now
Remember SONIC? Published in 2010 y @JeanFredericCo1

• IFX plus AZA was best
• IFX monotherapy was next best
• AZA monotherapy was worst

We said "what if cost was no barrier?"
Well ... we now live in that world
That's why AZA monotherapy is dead…
Step-up versus top-down in 2008!

The study that almost got it right? The clues were all there.

Early therapy is best.

A few tweaks to the design then and we could have shown what we now know to be true. There was too much here for the detractors!
CALM - @JeanFredericCo1 (again) 2018

Adalimumab early in the disease course with a treat-to-target paradigm
• mucosal healing rates of 45.9% at one year
• FCAL <250mcg/g most impt driver of Rx escalation

NOW a cost-effective option

We use ADA monoRx a lot for early Crohn's
SEAVUE - another early Crohn's disease study

Both ADA and USTE work really well

Excellent clinical remission and mucosal healing rates at one year

Better safety & PK profile for USTE
Importantly now we have many drugs that will heal the mucosa in Crohn's disease: IFX, ADA, USTE and VEDO of the licensed therapies

Most widespread definition is absence of ulcers

Mucosal healing remains THE treatment target in Crohn's disease
Anti-TNF drugs have been shown multiple times to be superb drugs to achieve mucosal healing

Nothing else could do this before they came along

We've had them >20 years now - only just starting to use them effectively!
USTE will heal the mucosa in Crohn's disease

The data from SEAVUE really add to this
VEDO also heals the mucosa in Crohn's disease

The data from VERSIFY (pictured) and CD-LOVE and VISIBLE 2 show this
The data on new molecules look very exciting too

The RIZA induction data show that mucosal healing is achieved by a significant proportion after induction only

The maintenance endoscopic data are even better

The drug works when anti-TNF have failed too - this is important
Soon we will also talk about effective dietary and microbiome therapeutics for Crohn's disease

I suspect for many these will be adjuncts to effective medical therapies

But for some they may be sufficient by themselves

We need much more quality research here
These slides are the basis of my talk on Crohn's disease: treatment principles and mucosal healing

It is recorded and uploaded here for you to watch:
Our team are working hard to produce many of these data

We are showing the benefit of
• biosimilars in IBD
• early effective therapy in Crohn's disease
• advance therapies in UC
• reduced surgical rates
• optimal use of T2T strategies based on FCAL

Lots more to come ..
Please leave comments below and go back to the top and share the first tweet ... this allows other to learn from the whole thread

The low down on Crohn's disease therapy:

• early effective therapy is key
• FCAL in year 1 is an excellent marker
• biosimilars make anti-TNF therapy an excellent option
• USTE & VEDO also good options for mucosal healing
• new therapies (esp anti-p19 eg RIZA) look superb
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