...what could happen ?

“And what are the side effects ?”

My dear patients,

 – that`s what pretty much all the patients with inflammatory bowel disease, Crohn`s disease or ulcerative colitis ask when starting biological therapy. The situation is always similar. When I start to explain that the previous therapy didn`t work out the way we need it for stable remission or that there is a need for starting efficient therapy anyway in the first place. I have my small speech “on the state of the union” and often … I look into 2 eyes beneath wrinkles on the forehead that get deeper and deeper. Corners of the mouth won`t make their way up anymore, you can grab the attitude of: “No ! Come on doctor – is that really necessary ?!”and than there is – of course! – the question: “And what are the side effects ?”

It is sometimes difficult for patients to see the chances and advantages of therapy. And often I recognize a rather “vague concern” about biologicals. When I ask: “what is it you are afraid of ?” the answers are hardly concrete. Which is ok.

I will give you some concrete information right away.

And maybe to start with so that we are not moving in the sphere of vague concerns and worries: side effects exist because the effects of antibody therapy and biologicals – same as every other medical preparation – don`t occur only in the gut.

Actually things in the gut are not different from  the  rest of the body. Especially the mechanisms of inflammation are the same almost everywhere in the body. Whenever the immunsystem gets activated pretty much the same thnigs happen. From the releasing of signal and transmitter  substances to the arriving of inflammatory cells in the inflamed tissue.

And of course, when you take an essential factor for inflammation as TNF alpha ( tumornecrosisfactor alpha) out if the game or reduce it`s efficiacy it makes a huge difference. Not only in the gut but in different sites of the body. In case of TNF alpha it leads to far less immune response and by that immune defence and inflammation. I wrote it in the lats article, the effects of Anti Integrins (Vedolizumab) or Anti Interleukin (Ustekinumab) is more special and by that in a way limited to certain steps of the inflammatory pathway.

In general there is a relevant risk of infection when taking biologicals.

... severe infection

Severe inflammation or severe infection is what patients are worried about in case of  biological or antibody therapy. And the risk for infection is there, espacially (but not only) for TNF alpha antibodies (Infliximab, Adalimumab, Golimumab). A normal infection can turn into a severe infection or even sepsis.

Sepsis is the state of inflammation when the body is not able anymore to  eliminate an infection that is ususally affecting just one organ (like the lung in case of pneumonia or the bladder in case of urinary tract infection) and by not being able to eliminate it, the infection spreads throughout the whole body.

That is a serious situation and when you read through the literature, generalized infection or sepsis is considered the most critical thing that can happen during treatment with biological therapy. But it is possible to minimize that risk, I will write below (*) how we can take care of that. 

Risk of infection is also about reactivation of hepatitis b or tuberculosis. These are infections the body can deal with very well “normally”.

And to whom of you who is about to think: ” yes, sure, tuberculosis…pretty far fetched isn`t it, doctor Weyrauch ?” I can only say “make no mistake”. It is very easy to inhale tuberculosis respectively the bacteria (Mycobacterium tuberculosis or also other Mycobacteria) and it is easy as well to get in touch with them in another way when you move around the big wide world.

And the big wide wold begins in front of your door. You don`t have to go on the “backpacking tour through india” vacation, you don`t have to go on the “rail ride  through russia to china” and no “discover africa off the beaten track” jouney either. As for many infectous diseases (I wrote about that in the article about vaccination) the body can deal with a whole lot it is confronted with. It can fight back a lot of infectous diseases or at least keep it under control (as with hepatitis b or tuberculosis) so that we do not even recognize that we are carrying the infection. In case you had contact with of tuberculosis you might see a small shadow in the CT scan, wich stays pretty much the same, at least doesn`t get bigger. This looks a whole lot different in case of immunosuppression with antibody therapy or biologicals, because the “shadow” won`t stay small then. The body is unable to keep it under control anymore and the infection is spreading throughout the body.

And there are not a lot of things I am “afraid of” or let`s say “have respect for” (since fear doesn`t help at any time), but tuberculosis definetly belongs to these category.

...the only way is 100% thoroughness !...

So infections are a risk and you have to keep an eye on it to 100%, whenever it occurs.

But mostly it is about the “small” infections. Patients report fungal infection, especial women fungal infection in the vaginal region.

Abscesses can develop. It is important to let other doctors, especially your dentist know about your immunosppressive therapy and especially your biological or antibody therapy. Especially when the dentist is planning an intervention it is wiser to take antibitiocs on a prophylactical basis (don`t worry about your gut, you can add some probiotics and you will be just fine) than having to deal with poorly heeling wound or an abscess.

But – from my perspective (I am not an IBD patient, but I know quite some of them) – most patients don`t have to deal with infections at all. The every day routine of patients with biological therapy is not that every other week they end up in hospital with severe pneumonia when others just catch a cold. And some or most of you will have recognized it already : you still get uncomplicated colds when you are under immunosuppressive or biological therapy.

The daily routine is not about patients being ill all the time during falland  winter or the early days of spring, hardly showing up at school or work and not being able to lead a normal life.

Patients learn to take care of themselfes and feel rather good, because IBD is under controll.

(*) Yet fever in case of antibody therapy or biological therapy is never (never, never, never, absolutely never !) something you can just wait for to dissapear as it came.

In case of fever you must see a doctor at least on the 2nd day of symptoms. And that may very well be your general practitioner, that doesn´t have to be your gastroenterologist. It is necessary to make a physical examination, to examinate the lung with a stethoscope, to check a urin status, and to takle a blood sample. For example urinary tract infection that is not treated adequatly right away  (antibiotocs!) can really cause serious problems and spread over the kidneys throughout  the whole body. Which leads us to the topic of sepsis again…

Sometimes you have to perform a CT scan to know, wheter there is an infection in the lung or somewhere else in your body. Especially in the lung there is a chance of “atypical” pneumonia, which can be diagnosed only by CT scan and which – as the name “atypical” pneumonia suggests it – will not necessarily lead to typilcal symptoms as fever and coughing pneumonia normaly does. 

Under biological therapy (again mostly TNF alpha antibodies or combination of biologicals and for example azathioprine or corticosteroids) there is also a risk of opportunistic infections, which you do not catch up when having a normal immune status.

So in case of fever: always go to see your general practitioner right away. 

Is it a little annoying sometime to always immediatly call the doctor and see him or her ?

It definetly is.

Can we then just …well let`s say wait and see, if the fever might get better, let`s say after 3 days or over the weekend ?

No way !

Of course it is annoying, especially in times when all kinds of infections are out there (which means many different ones not just the one we hear about on the news all the time) and when you by chance have to see your doctor several times in one month or in even shorter periods in time. But it is absolutely necessary.  Because when you are under antibody therapy, some things that are harmless under normal circumstances can turn out to be very nasty.

Please stay absolutely carefull and thoroughly here. 100%

... what else ?

Another side effect patients hardly ask me about, but wich I always mention: allergic reactions.

They can occur during any biological therapy and even after 265 infusions without a problem the 266th can end up with an allergic reaction. Severe allergic or even anaphylactic reactions occur usually during or shortly after infusion. That`s why  infusions must be performed in a  docotor`s office or an outpatient clinic or a hospital in the presence of a doctor (in the sense that a doctor is at least around).

Heartbeating with a high heart rate, flush, hypotension, sudden difficulty in breathing, feeling unwell with nausea and fever might occur as symptoms of an acute allergic reaction.

(When biologicals for example infliximab infusion are given too fast it can also cause discomfort). 

Allergic reactions can also occur 2-3 days after infusion.

It is possible to prevent these reactions by giving a rather low dose of corticosteroids before the infusion (intravenous). That`s a practice sometimes performed, often just for the first 3 or 4 infusions. In that situation it might help, but it won`t do anything at a later point in time or a later infusion since – as said before  – allergic reactions can occur anytime.

Another thing many patients worry about is: malignant disease. Lymphoma, malignoma, malignant tumors. In the package insert or at least in the medical expert information it actually says that “an elevated risk for carcinoma can not be excluded“.

Well… when these kind of information or let me say messages are out in the world they won`t dissapear that fast. And in patients heads they take quite a lot of space. And if I wrote: forget it, just not true ! here, you would not just believe me. There would still be some doubt.

... fear of malignat diseases ?

So let me start with leting you know what you can do, to minimize the risk for the one malignoma that really seems to be associated with use of immunosuppressants and some biologicals.

Please avoid sun bathing, exposition to the sun and UV-radiation.

Some biologicals can increase the risk for skin cancer (azathioprin as well). Patients with TNF alpha antibody therapy should see the dermatologist every year.  And on a day to day basis  always take care about UV protection.   Whenever you are exposed to UV light, use sun block, wear clothes that protect your skin. That doesn`t just mean the summer vaccation on the beach during the warm months. In case you receive antibody therapy  sun bathing or sun exposition  is just not the right thing to do (as for anybody else in general). You really have to be very carefull there.

And other malignat tumors ? There are actually quite a few studies that seem to show that antibody or biological therapies do not make a difference.

I do not want to go too far here, because  – as I said or wrote before –  in some cases it is written black on white in some information sheet. But again and again research seems to not confirm that. And another thing is that we do know the TNF alpha antibodies for 20 years now. They are not only used for patients with IBD but also for other chronical illnesses like  rheumatoid arthritis as well.

What I want to say is: these are not medical substances for some orphan diseases that just a handfulll of people receives worldwide so that you actually don´t know what problems the medication causes, because numbers of people who are treated are so low. These are very common therapies, we should be clear on that.

And I always tell my patients : what increases your risk for colon cancer in case of ulcerative colitis is not the biological therapy ! It is an not sufficiently treated  inflammation in your gut that`s going on for years.

So that are the most common worries patients have about biologic therapy.

a lot of insecurity, questions, concerns - little side effects

Another issue that patients are very anxious about is – especialy in young patients of course – the issue of familiy planing and the desire to have children. That is more about  the risks of therapy than about side feffects and I will definetly write an extra article on that topic at one point.

For today: for women as well as for men there is no definite evidence for relevant increased risks under biological therapy (exemption: tofacitinib). Especially during pregnancy: the dangerous thing is the flare. It is not dangerous to get pregnant in stable remission and have biologic medication until the 3. Trimenon or even longer when necessary. Data are really good for that.

What else ?

TNF alpha antibodies can cause heart insuficiency. Very rare, but whenever one of my IBD patients complains about short breath or about swollen ancles weeks or months after having started TNF alpha antibody therapy I send him to the cardiologist to perform an ultrasound examination of the heart. Until now, it always turned out to be fatigue or irons deficiency or anemia. But we should always consider this rare side effect of  TNF alpha antibody therapy.

And TNF alpha antibodies can cause joint pain. Which is kind of tricky since joint pain and arthritis can as well occur as an extraintestinal manifestation of IBD

For tofacitinib an elevated rate for thrombosis and pulmonary embolism is desribed. Which are serious events and your doctor should have talked to you about it in case you receive that medication.

Finally something I find important as well even though it is not a side effect and it is not a risk in the sense of the meaning either. It is more someting in the category of #justhappens@toobad.com. And unfortunatly it means the need for changing the therapy.

I am talking about the situation when the body creates antibodies against the antibody therapy.

Antibodies against the antibody ?

Getting pretty strange here ?

Antibodies not in the sense that they cause an allergic reaction and you feel immediatly bad as described above. But rather in a way where the body defends itself against the “strange” medication. By neutralising the medication that is the antibody therapy.

And some of you might know it and have experienced it: there are situations, in which medication doesn`t seem to work anymore. Also during treatment with biologicals there can be an increased disease activity. Then we have to find out why that is so. There are several possible reasons for that, which I do  not want to list and discuss here, because that would turn out to be an extra blog article. But one reason for a deteriorating of effectiveness of the therapy are – antibodies.

These antibodies develop without you even recognizing it (except recognizing a poor response to therapy – which is adnittetly not little). The body develops these antibodies secretly and silently and neutralizes the antibodies gicen as medication. Whenever you receive biological therapy as an infusion or injection, these antibodies, which the body creates neutralize the antibody  therapy you receive as a medication. That is also more frequent in TNF alpha antibody therapy than im other therapies.

These antibodies can be measured in the blood (often together with the so called trough level in the blood to know wether there is enough of the medical substance in the body).

In case of high elevation antibodies you have to switch therapy. (in case of low antibody titers you can eventually muddle through…). And: not everybody develops antibodies ! It is possible but not obligatory.

So far for risks and side effects of biological therapy for today.

In case someone takes out the package insert of ustekinumab now and reads through the table with the side effects in terms of “rare”, “common”, “very common” – yes, you will find things I didn`t mention here. For vedolizumab the same.

I intended to focus on the “feared” side effects

All in all –  and I think when you read through this blog frequently you might already have guessed that – I really favor this biological therapies. Because they have a very good effect for very many patients. They can give back life quality  to patients and stabilize the illness. That prevails risk for side effects by far in my opinion.

While I was writing this article, in Bavaria season has turned into a pretty grey and cold November, Covid numbers are rising, everybody is a little stressed out and especially my IBD patients are stressed out as well. Which brings me to write my next article on how stress influences IBD. As a matter of fact !

So until next time once again take care,

Best regards,

Yours

Dr. med. Susanne Weyrauch

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