# Switching Anti-TNF Agents: Evidence-Based Results and Clinical Experience



## David

The article, "Switching Anti-TNF Agents: Evidence-Based Results and Clinical Experience" by Remo Panaccione is found on pages 683-686 of the book, "Advanced Therapy in Inflammatory Bowel Disease" and is supported by 22 references.  For any of you interested in the deeper medical side of Crohn's Disease, this book is fantastic but be warned, it is aimed at medical practitioners and is heavy reading.  This thread will contain information I feel is useful in the article and I also open it up for discussion.

- The reasons for switching anti-tnf might include: primary non-response when first starting the medication, loss of response after some duration, intolerance to a medication, or interruption of doses.

- When you switch from one anti-tnf to another, there is no need for a delay between doses to let the other medication exit your system and you should get a full induction dose.

- Some people want to switch from infliximab (Remicade) to adalimumab (Humira) or certolizumab pegol (Cimzia) because they allow for self-injecting even when they're having a good response to Remicade.  While there is no data on this, it is not advised.  The primary reason is they feel if you lose response to the new medication, there's a good chance you'll lose response to the old medication as well due to immunogenicity (you develop antibodies to it).  So you'd lose out on two medications.  It is also not advised to switch from Humira or Cimzia to Remicade for the same reasons.

- One third of patients will not respond to anti-tnf therapy.  

- If you don't respond to a biologic, you are a "Primary nonresponder".

- If you don't appear to be responding to a biologic, it's important that your physician make sure it's not due to something else such as, strictures, fistulae, abscesses, c.diff, small intestine bacterial overgrown (SIBO), CMV, bile salt diarrhea, etc.

- You should have your full induction dosing before being termed a primary nonresponder.  

- For Remicade, some suggest the full induction dose then, at the 6 week dose, double the dose before determining non-response.

- For Humira, it is suggested to wait a full 12 weeks before determining non-response.

- Sometimes people with Crohn's don't respond well to anti-tnf because that's not the primary component of their inflammatory response.  In that is suspected as the reason for a primary non-response, trying natalizumab (Tysabri) may be worthwhile as it isn't an tnf blocker and has shown efficacy when people fail anti-tnf therapy.  It does increase the risk of progressive multifocal leukoencephalopathy (PML) so that risk needs to be weighed.

- Of those who initially respond to anti-tnf medications, 40-50% will stop responding within 12 months 

- Thereafter, data shows that 10-15% will lose response on a year by year basis.

- When you experience a secondary loss of response, you can increase the dose, shorten the interval between doses, switch to another anti-tnf, or switch to another type of medication.

- Just as with primary nonresponders, it is important that your doctor make sure that you're not experiencing symptoms that are not actually indicative of loss of response.

- At the time of the article, only antibodies to Remicade could be tested for.  I'm curious of they have tests for Humira and Cimzia yet.

- If someone appears to be losing response, making sure that inflammation is back via CRP, ESR, increased platelets, fecal calprotectin is important so as to rule out other causes such as infection.

- The author suggests someone who appears to stop responding should be evaluated via colonoscopy, capsule endoscopy, CTE, or MRE as well.

- A study out of the Mayo Clinic found that about 50% of people with symptoms of a flare were not actually inflamed and it was coming from some other cause.

- For people on Remicade who start to lose response and are negative on antibodies but have no or no detectable serum levels of the medication, increasing the dose or shortening the interval may work well.

- If someone is on Remicade and get symptoms not long after an infusion, then a dose increase is probably the best bet.  If they do well until just before the next infusion, then shortening the interval would likely be best.

- Increasing the dose has been shown to help about 80% of people who start to lose response.

- For Humira, increases the dose from 40mg every other week to 40mg every week helps about 50% of people.

- In Cimzia, the dose changes from 400mg every 4 weeks to 400mg every 2 weeks.

- If you are found to have antibodies to Remicade but were initially a responder, then switching to another anti-tnf is likely the best bet.

- One study (GAIN) showed switching from Remicade to Humira was better than placebo and one study (WELCOME) found the same for switching from Cimzia to Remicade.

- If someone has a reaction to infusions, often the best option is to treat that reaction.  Minor reactions such as rash, flushing, minor chest pain, or dyspnea (shortness of breath) can be treated beforehand with steroids, antihistamines, or tylenol depending on the reaction at the previous infusion.

- If someone has reactions to Remicade, it's important to test for antibodies as those type of reactions tend to get worse over time.

- Changes in vital signs, severe chest pain, and anaphylactoid reactions warrant changing medications to a different anti-tnf.

- Many people get skin problems such as folliculitis, pseudopsoriasis, palmar-plantar pustulosis, or psoriasis.  These usually don't warrant switching to a new medication and a dermatologist can help control them.

- Arthritis, arthralgia, lupus-like syndrome, and drug induced lupus are relative common with anti-tnf medications.  Many in fact develop antinuclear antibodies and anti- double stranded DNA antibodies.  It is not felt that this is cause to switch to another medication but a rheumatologist should be consulted.  If someone develops drug induced lupus, then a switch should be made.  It is felt the chance of drug induced lupus with Cimzia is much less so a switch to it is logical.

- Sometimes people will have surgery which interrupts the dosing of the biologic.  Any dose interruption may cause development of antibodies.  The suggestion is to go back on the original medication if they were responding well to it.  If possible, first measure for antibodies.  

Good article.


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## Clash

Thanks , David I really appreciates all of your posts on articles out of this book. I'm going  tag jmckinley since this seems to appt to the reaction their lo just had.


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## Wooddy

David said:


> - A study out of the Mayo Clinic found that about 50% of people with symptoms of a flare were not actually inflamed and it was coming from some other cause.
> 
> 
> Good article.


Very interesting, what were the parameters of this study?  Did the 50% that didn't have inflammation demonstrate any common symptoms?  Is there a copy of the study available?  I would like to read it.


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## David

Wooddy said:


> Very interesting, what were the parameters of this study?  Did the 50% that didn't have inflammation demonstrate any common symptoms?  Is there a copy of the study available?  I would like to read it.


This is the study they reference but I don't have access to the whole thing.  Maybe you or someone else does.


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## Wooddy

Ok, I just read the abstract and it piqued my interest even more.  Gonna check the library for that journal next time I am there.


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## jmckinley

David, 

Can the amount of antibodies decrease? My son's Remicade antibody level was 5.6 in June. It is now less than 3.1. I am hoping this is true and not an error of some kind, but I was not aware that they could decrease. He did start taking methotrexate when the level was found to be 5.6.


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## David

That's a really good question, one I don't know the answer to.  I did some poking around and couldn't find any papers or studies where they come out and say that the antibody level is decreased.  This is the most pertinent paper I could find which may help you a little.

Next time you see or talk to your doctor, will you ask them?  I'm quite curious what their answer is.

Sorry I couldn't be more help


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## DustyKat

jmckinley, David, I have only been able to find this thus far. The study numbers are small:



> Pariente, et al. (2012) reported that trough levels and antibodies to infliximab did not predict response to intensification of infliximab therapy in patients with inflammatory bowel disease. The investigators sought to assess the clinical value of measuring infliximab trough levels and antibodies to infliximab concentrations in IBD patients who lost response to infliximab therapy. The investigators retrospectively studied records of IBD patients who lost response to infliximab therapy. The investigators first assessed clinical responses of different therapeutic strategies that were applied when patients lost response to infliximab and then we looked at the correlation between clinical response and infliximab trough levels and infliximab antibody concentrations. The investigators reported that 76 IBD patients were included.; 31 patients (41%) continued infliximab therapy without any modification, 39 patients (51%) had an intensification of infliximab therapy, five patients (7%) had switched to adalimumab therapy, and one patient (1%) underwent surgery. Clinical response was observed in 27 patients (69%) with an intensification of infliximab therapy. The investigators found no significant difference in mean infliximab trough level at inclusion in patients who responded to intensification of infliximab therapy (3.3 + 4.1 mcg/mL) as compared with patients who did not respond (2.3 + 2.2 mcg/mL, p = 0.85). In all, 16/76 patients (22.4%) presented detectable infliximab antibodies in the serum. Ten antibody-positive patients had an intensification of infliximab therapy and six (60%) demonstrated a clinical response. *After intensification of infliximab therapy the infliximab antibody concentration decreased in five patients. The investigators concluded that, in patients with IBD who lose response to infliximab, clinical improvement may occur upon intensification of infliximab therapy, irrespective of infliximab serum concentration or presence of infliximab antibodies.*
> 
> Source


Dusty.


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## jmckinley

"HACA appeared to be associated with lower serum infliximab concentrations"

David, this is from the article you shared. With the first HACA test, Ryan's remicade levels were undetectable. They increased is dosage and added methotrexate as a result. With the second HACA tests (which showed less antibodies), his remicade levels were good. May be the cause of the change?

I will ask the GI. I asked the nurse but she said, Hmmm...I don't know.....


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## David

It could be the higher dose, it could be the methotrexate, or it could be a combination.  Heck, it could be some unknown variable.  But the previous line in that paper provides a theory for the reason for lower HACA with higher dose:



> Formation of HACA may be inversely related to the infliximab dose. HACA were found in 53, 21, and 7% of patients with RA receiving infliximab 1, 3, or 10 mg/kg, respectively, 12 weeks after the last of five infusions of the drug.7 *It has been suggested that higher doses may be associated with immunological tolerance*.


I don't understand why that would be, but it's quite interesting.

Please let us know what the GI says, I'm quite curious.


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## Wooddy

jmckinley

The studies (abstracts) referenced in the links below also suggest that there is more evidence to back David's suspicion that the addition of methotrexate helped. 

http://www.ncbi.nlm.nih.gov/pubmed/15097438

http://www.ncbi.nlm.nih.gov/pubmed/16357613

It also seems like more is going on here, it's curious that some responded to a dose increase over others.  I wonder epitope mapping was included in any of the studies that correlated HACA levels with dose and response.


I am glad that your son has responded better with the addition of methotrexate.  Also, while he is on it, it's especially important to talk to your son's doctor about supplementing his diet with folic acid if he isn't already.


I am curious to hear what his doctor has to say as well.

Good luck


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## suschex

- A study out of the Mayo Clinic found that about 50% of people with symptoms of a flare were not actually inflamed and it was coming from some other cause.

Good article.

I am curious what other issues could have caused symptoms in the 50% who had no inflammation.  I know they always check my stool for c-diff, bacterial infection, etc. but are there other things that mimic a flare?  It is so hard to "feel" as if you know what you are experiencing in your GI tract only to be so wrong once they go in and look around.  It is like loosing credibility when it comes to your own body!


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## David

Suschex,

Here is the study that they reference.  In that study, they say:





> In the presence of therapeutic infliximab concentrations and clinical symptoms, confirmatory testing with ileocolonoscopy and / or computed tomography or magnetic resonance imaging enterography should be performed. To underscore this recommendation, in patients with clinical symptoms and a therapeutic infliximab concentration, patients continued at the same dose 76 % of the time and had no evidence of active inflammation by endoscopic / radiographic assessment 62 % of the time. Increasing the dose or changing to another anti-TNF agent in these patients would have led to inappropriate management. If therapeutic infliximab concentrations are present and there is persistent disease, then increasing the dose of infliximab or changing to another anti-TNF with the same mechanism of action would likely be of little benefit, and consideration should be given to switching to a medication with a different mechanism of action.


So basically they're saying people will often be at the therapeutic level for Remicade, exhibit symptoms, but when they check for active inflammation, there isn't any.  They don't say what they think the potential causes could be though.

I reread the article I reviewed and they state: 





> There are several points to make about primary non-response.  First, it is important to exclude alternative causes of symptoms, including strictures, fistulas, abscesses, bile salt diarrhea, steatorrhea, small bowel bacterial overgrowth, IBS, c.diff, cytomegalovirus.


While that's not specifically to what was being discussed, those are some of the potential causes of symptoms other than active inflammation.


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## BionicBelly

Stelara should be coming in the next couple years for people who are primary non-responders to anti-TNF drugs:

this site won't let me post a link to the article.  It's in stone hearth newsletters dotcom (all one word).  Go to that site and search stelara and you can see the article about it.

"Ustekinumab, an antibody proven to treat the skin condition psoriasis, has now shown positive results in decreasing the debilitating effects of Crohn’s Disease, according to researchers at the University of California San Diego, School of Medicine.  The study will appear in the October 18, 2012 issue of the New England Journal of Medicine (NEJM).

"


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## Clash

BionicBelly, we actually have a some members that have tried stelara. If you click on the highlighted words in your above post it will take you to our wiki forum which has information, studies and such on the drug. Also at the bottom of that page there are threads listed that mention stelera such as this one(<----click here).


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## BionicBelly

Thanks, just wanted people on this thread to be aware that Stelara could be an option if they don't respond to any of the anti-TNF drugs.   A lot of people either don't respond at all, or only for a relatively short while.  From the article I can't post a link to:

"“Our biggest challenge in treating patients with Crohn’s Disease is managing patients whose bodies are resistant to tumor necrosis factor (TNF) inhibitors such as Remicade, Humira and Cimzia,” said Sanborn, MD, principal investigator and chief of the Division of Gastroenterology at the UC San Diego School of Medicine.  “Ustekinumab blocks two proteins that cause inflammation, interleukin 12 and 23.  This finding is a significant first step towards a new treatment option for these patients."

One third of patients with moderate-to-severe Crohn’s Disease do not respond to current treatment with TNF inhibitors, which regulates the body’s immune system and inflammation.  Another one third of patients only have a temporary response."


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## Clash

Yes, you have to have a certain number of posts before you can post a link but thanks for providing information about stelara. When you reach that number of posts if you would like to start a thread about stelara and the experience or info you have about it in the treatment forum that would be great too.

Also, just wanted to welcome you to the forum!


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## Patricia56

Hi David,

Are you familiar with this website? I find it quite interesting and helpful.

http://www.ibdwg.org/


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## David

I've seen it before but haven't taken the time to delve into it.  Thanks for the reminder!


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## Patricia56

I find it a pain to navigate the site. Regularly have to sign back in and there are sections where there are no labels so you just have to pick an item and open it to find out what's inside.

But the content keeps me coming back. It's written by the top researchers (Sandborn) for each other and other physicians. Much of it is power point style presentations that summarize and analyze research findings, often synthesizing the results from multiple trials together and reconciling it with existing practice and understanding.


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