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Crohn's Disease Forum » Books, Multimedia, Research & News » De Novo Anti-TNF Therapy in Crohn's Disease: Evidence Based Results


10-05-2012, 06:52 PM   #1
David
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De Novo Anti-TNF Therapy in Crohn's Disease: Evidence Based Results

The article, "De Novo Anti-TNF Therapy in Crohn's Disease: Evidence Based Results and Clinical Experience" by Stephen B. Hanauer is found on pages 677-682 of the book, "Advanced Therapy in Inflammatory Bowel Disease" and is supported by 44 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.

- Infliximab (Remicade) trials have shown it reduces the number of draining fistulas or stops their draining and maintains that whether or not other medications are used at the same time.
- Adalimumab (Humira) and Certolizumab (Cimzia) trials have shown they work at maintaining fistula closure, but not as well as Remicade.
- The shorter a patients disease duration, the better they responded to the above mentioned biologics and thus they had better overall outcomes. [David opinion - A good argument for the top down approach]
- Immunogenicity is when the medication evokes an immune response. This isn't uncommon with the biologics.
- Because Remicade is a chimeric antibody it is at greatest risk of immunogenicity.
- Small starting doses and episodic treatment bring about immunogenicity more. High loading doses and regular scheduled doses has reduced this issue.
- At one point studies resulted in biologics and immunosuppressives such as 6-MP and Azathioprine not being used together. However, that data is now somewhat ignored as there was a lack of proper randomization.
- In the COMMIT trial patients were given Remicade alone or Remicade with Methotrexate. At 14 and 52 weeks, there was no difference in how many patients were off steroids.
- In the SONIC trial patients received azathioprine alone, Remicade and Azathioprine, or just Remicade. Patients had Crohn's for an average of two years. 31% of patients just on azathioprine achieved steroid free remission at 26 weeks versus 57% of the patients on azathioprine AND Remicade and 44% of patients just on Remicade. The groups on Remicade showed rates of mucosal healing at 44% and 30% respectively versus 17% of those only taking Azathioprine. There is an important editors note however that states that azathioprine and 6-MP have much higher rates of remission in other trials as all patients in the SONIC trial were rapid metabolizers.
- There is little evidence that Remicade or immunosuppressives stop fibrotic strictures from forming or benefit people with existing strictures.
- There is evidence that a "Top Down" approach may be beneficial to those who are at greater risk for a "severe" or "progressive" disease. The groups are: early onset disease, fistula/obstructions early in the disease, deep ulcerations, need for steroids, high serologic markers such as ASCA.
- The SONIC trial showcased that biologic therapy helped people with visible ileocolonic ulcerations and high CRP a Lot. Conversely, people who didn't have mucosal lesions or elevated CRP did no better with Remicade. Interesting!
- TNF production may change during the course of the disease.
- The author utilizes concentrations of Remicade and antibodies to determine if there has been a loss of response.
- The author states that it is important to understand antibody/antigen excess when determining the timing of tests. After a biologic is given, there will be an excess of antigen and there shouldn't be any antibodies so wait 4 weeks before testing for antibodies. They feel if, four weeks after an infusion a patient is flaring and has antibodies to the biologic present, then they should be switched to a new biologic. If someone is flaring but doesn't have antibodies then the dose can be increased or the duration time shortened.
- The author monitors response with CRP on the short term and colonoscopy on a longer term to see if there is mucosal healing.
- About 50% of the authors patients need increased doses or shorter intervals of Remicade.
- If someone has an injection site reaction to Remicade and flare, they likely have antibodies. Patients who flare at the end of a dosing cycle should likely have an increased dose or shorter duration.
- In young men who have been on and failed azathioprine or 6-MP and move on to biologics, the author works to get them off the thiopurine within 6-12 months to reduce risks of cancer. They stay on that long to reduce the risk of immunogenicity.
- Biologics should not be started in someone with an active infection or abscess and should avoid live vaccines.
- TB testing and a chest xray should be performed prior to initiation of biologic therapy.
- Monitoring for infection while a patient is on biologics is important.
- Humira and Remicade cross the placenta and are usually ceased at 20 weeks of pregnancy. Cimzia is less likely to cross the placenta. There are no known effects to fetuses but live vaccines should be given at a later than normal date once the baby is born.
- A new biologic in testing, ustekinumab (Stelara) is showing promise in trials where people have failed 1-3 other anti-tnf agents.
11-10-2012, 03:49 PM   #2
mreyn
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David, You seem to be very knowledgable about all this... My question is.. my son is 12 and started on Remicade...they want to add Imuran but due to the side effects we are probably going to not add Imuran. In your opinion from all the medical literature.. what would be best and safest for a boy that age? Remicade alone or Remicade/Imuran combo (which has the black box warning for using combo in young boys?)

We want to do whats best for our son.
11-10-2012, 07:42 PM   #3
David
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mreyn, I'm not comfortable with your use of, "very". I think i'd prefer, "sorta".

You have such a hard decision to make, my heart goes out to you I can't imagine how hard it is and I think it's great that you're doing what research you can. I wish I could say, "X" or "Y" but there are so many variables to take into account to determine what is right for your son. For example, if he is responding well with Remicade and doesn't appear to be having an immunogenic response (making antibodies) then pure Remicade would likely be best. If your son has been on Cimzia and Humira and ended up losing response due to immunogenicity and Remicade is his last option and his Crohn's is severe, then I could see utilizing Imuran as well.

It's hard to weigh the various variables to determine where the most risk lies and what course of treatment is therefore safest. Hopefully that's something your doctors are explaining in depth to you. If not, getting an additional expert opinion in such cases would certainly be understandable.

I wish I was more help I guess in the end the big question for your doctors regarding adding the Imuran is "WHY" and why do they feel the risks from such a combo are outweighed by not utilizing that combo.
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