Antibodies, Biologicals, Biosimilars

My dear patients !

Then …  about 20 years… once upon a time ….

The year 2000, sound like everything was possible then, right ?

Whoever of you lived with inflammatory bowel disease, Crohn`s disease or ulcerative colitis then might remember the time. And might remember it maybe not as the best  time for having this illness and receiving medical therapy.

I was still at medical school back then, somewhere in a medical clerkship on a surgical ward at the university clinic in Lübeck. And it was actually then, when I saw patients with inflammatory bowel disease, Crohn`s disease or ulcerative colitis for the first time. Which means I recognized them as patients in a special situation with this disaese.  But since then I do have a much better perspective and understanding on what these disease is about.

Have you reconize it ?

I made my first experiences with IBD patients on a surgical ward. About 20 years ago.

Not in a gastroenterologic outpatient clinic, where patient received therapy. The point is that a heavy flare of either Crohn`s disease or ulcerative colitis ended up as a surgical case very quickly at that time. Either cortison was able to fix the problem, maybe with a little support of mesalazin and azathioprin. But when all this didn`help the colon was gone very quickly and also in case of Crohn`s disaease surgery was performed more often.

And to come to the biologicals or antibody therapy: about 4 years later (once upon a time…. The story took place at the university hospital in Tübingen now, me in my first year of work at a gastroenterologic outpatient clinic) the first patients came to receive infliximab. In a number of 2 to maximum 4 per month. That was rare (I remember having to read what to consider when giving infliximab infusion again and agian, because the time lag between two patients was so long.) And that was a university hospital with a commited senior physician with a special consultation hour for IBD patients. Today almost every gastroenterologist has a couple of patients with inflammatory bowel disease, Crohn`s diesease or ulcerative colitis in the consultation hour or sees them while performing endoskopy, who receive biologal therapy (even if not every doctor offers infusion in his doctors office).

...Antibodies, Biologicals, Biosimilars

So, there has been quite some change in the field of IBD therapy since then. The introduction of antibody therapy was the decicive step. And with that in mind let´s have a look at the  – meanwhile not that new anymore – biological or antibody therapies.

I always use the term antibody therapies. Antibody and biological therapy means exactly the samen. And in case you hear or have heard the term “biosimilars” at any point or have heard it already, it is the same as well. These are the generics. As for today`s status they exist only for infliximab and adalimumab. But you don`t have to be a clairvoyant  to know, that this will change.

A couple of years ago I would have ensured everybody at this point: they are helping and are exactly as effectice as the original infliximab or adalimumab. That is not necessarry anymore. I think probably even most of you are receiving biosimilars without having a need to discuss it since it just works.

Antibodies/ biologicals / biosimilars affect certain inflammatory pathways by inhibiting them in one way or the other.

Because what´s causing inflammatory bowel disease, (maybe boring already, I know, I am writing it in each blog article) Crohn`s disease or ulcerative colitis is an exaggerated immune reaction – mainly in the gut (more to that “mainly” in the article about extraintestinal manifestations). A reaction of the bodies defence, nothing less than inflammation. And the problem is, that the body can`t take countermeasures, as it usually does in that situation.

TNF-alpha-Antibodies...

The TNF alpha antibodies wich are used for therapy in case of inflammatory bowel disease are Infliximab, Adalimumab and Golimumab. TNF alpha (long version: tumornecrosisfactor alpha, short version TNF-a – not for memoryzing but for having read it and heard about it) is a protein, that is working as a signal messanger or regulating messanger for inflammation. It is transmitting signals, which are essential for many or even most mechanisms that take place in case of immune response and with that in inflammation. Without these signals mediated by TNF alpha there is no inflammation. And that`s why these medical substances work that well – there is just no inflammation.

Inflammatory cells don`t know where they should turn to, they are not able to release proinflammatory substances to keep inflammation running, they can`t call for other inflammatory cells to help them create more inflammation.

That the whole issue of inflammation  could be checked off under the title INFORMATION MATTERS should be mentioned only in passing here: no information, no communication – no inflammation.

It is pretty much the same thing with the other antibodie therapies / biologicals. They also intervene in the mechanisms of inflammation

...Vedolizumab

Vedolizumab (belongs to the subgroup of Integrin-antibodies, analogous to TNF alpha antibodies) has it`s effect in intervening while inflammatory cells leave the blood vessels to migrate into the inflamed tissue. In case of inflammatory bowel disease it is mostly gut mucosa.

Inflammatory cells (white blood cells or leukocytes) are always ciculating in the blood. In case of inflammation their number increases and they are directed to the site of inflammation  by certain signals, where they leave the blood vessel into the tissue. And in order to do that, they hook up to the cells of the blood vessel wall.

I don`t want to go into details here but – as everything in the body without exemption – this is a very well thought out and precise mechanism, that makes me smile while I am wrtinig this. No kidding. And I am not ignorant here, I know, that whoever reads this thinks: “well, thank for talking but what exactly do you consider “good” in inflammation ? You might get the experience of having IBD instead of just writing about it, Dr. Weyrauch… “. Got that.

All I want to say is: the human body is a miracle. Nothing less. It is always wise, everything is arraged perfectly. And even if one thing is not working right, the rest is still fullfilling it`s job in most cases. And I would like to draw your attention to the following, without meaning to offend anyone or to play something down: Yes, your immunsystem is causing you troubles with your IBD. But – and I do not know wether this is helpfull – at the same time a lot of things in your body are working perfectly well. With or without chronical illness we are allowed to recognize that every once in a while.

What was I about to write ?

Ah yes, Vedolizumab as an integrin-antibody and the inflammatory cells migrating from the blood vessels into the tissue. And for doing so having to attache to the vessel wall. So the integrins are certain molecules, that help them to attache to the vessel wall – just like little anchors – in order to leave the blood vessel and migrate into the tissue. Beeing an integrin antibody Vedolizumab is blocking these “anchor molecules”. As a consequence cells cannot hang on to the vessel wall and according to that cannot migrate to where inflammation is happening. No inflammatory cells – no inflammationm, simple as that.

Ustekinumab and Tofacitinib

Ustekinumab works by blocking two proteins (called interleukins, which gives them the name “interleukin antibodies“).These interleukins participate, influence and regulate inflamatory processes. In the whole same as TNF alpha antibodies, except the blocked proteins are more specific in a way. Smaller maybe. TNF alpha is involved in many if not all  what is important for inflammation.

Integrins and interleukins are important as well but rather for single steps in a cascade. That`s how it can maybe be explained best.

I almost forgot Tofacitinib. That is blocking and inhibiting mediators of inflammation (so called cytokines). In case of Tofacitinib you don`t talk about antibodies but rather say JAK-Inhibitors. The mode of action is the same.

... what is going on ?!

That was a rather rough overview of the mode of action of antibody therapies or biologicals. But that`s how it can be described so that you have a more concrete idea “what`s going on there”, if you receive these certain therapies.

It is about giving you an idea so that you can have a better understanding rather than describing the whole signal transduction pathway in detail.

As maybe all of you know all the antibody therapies are given as an infusion or an injection. Except Tofacitinib, but as a tablet it is also resorbed in the gut and dsitributed in the whole body. And yes, that´s what brings us to the side effects fron these therapies.

So next time about the side effects

Take care and best regards !

Yours, Dr. med Susanne Weyrauch

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