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PANEL: Mettler, Braverman, Gomel

PANEL: Mettler, Braverman, Gomel

Endometriosis Foundation of America 2014
Outsmarting Endo - Panel #1
- Drs. Gomel, Braverman & Mettler

Audience Member: I am just curious, you mentioned T-cells and the way that they work and the way that they stop pregnancy from ____ into the uterine lining to become a pregnancy. My question is, is that related to, it was a few years ago probably about 15 or 16 years ago that Dr. _____ was doing a study on antibodies. Is that the same type of...

Dr. Braverman: No. I have to tell you 15, 16 years ago we did not know anything about this. Anything done about 15 years ago you just sort of have to throw in the garbage. We just had no idea how complicated immune interactions with pregnancies were. And the people who were doing these studies were not immunologists. The biggest problem with this field is that people are looking at one isolated cell, one isolated antibody and doing all of these studies to look for associations and you cannot do that. You really have to look at the entire immune system as a whole because that is how it functions. I do not know the study that you are speaking about, maybe it was antiphospholipid antibodies because they really had the most popularity and there was really excellent work done. It was groundbreaking because back then we did not know that much.

Dr. Abrams did a lot of great work on this and we actually have a very big seminar coming up in June from the American Society of Reproductive Immunology. I will be the co-chair of this meeting. It is going to be _______. We are going to have all the scientists from around the world who are working on small portions of all of this come together. And this is the very first year and the reason they asked me to co-chair the meeting is because they want to start getting into the clinical realm. They need somebody to put all this together and start applying it clinically.

So, I cannot answer the question because I am not really sure what it is but I hope I approached it.

Dr. Mettler: May I just ask about your etiquette of patients? I have been in that field so long and all these studies you present are very expensive. I would like to know from you really what are you treating the patients with? You say immunomodulatory treatment, can you give an example? Hashimoto I understand but what other treatments are you giving the patients to verify these expensive tests? There is a whole panel and many doctors do all these tests and I want to know what is your consequence, what are you giving the patients as a consequence from immunomodulatory treatment to improve their fertility?

Dr. Braverman: Okay. One of the things that I brought up that we found, and by the way there are so many different areas because it is very rarely one diagnosis, in other words, we look at endometriosis as an autoimmune issue. But if we see that, for instance, we think it is an antibody mediated syndrome we try to reduce antibody production. We give them Prednisone, we give them intravenous ____ globulins, anything to reduce. And we see all the immune parameters in some of the women when they are in a very strong TH2 dominant state. We reduce the antibody production. If we see the T-cells are activated, we see the IP10 levels are high and we know there is T-cell activation we use intralipids have become very famous, probably over used, but intralipids do an excellent job of preventing naïve T-cells from becoming cytotoxic T-cells. So when we see these levels that are elevated we treat these and they come down and we see success. Natural killer cells we know are elevated in patients with endometriosis. We see this fairly consistently. We do not know if the natural killer cells are a direct attack against the pregnancy or whether they are a moderator through something called antibody dependent cellular cytotoxicity. Antibodies bind, NK cells bond to the antibodies, carry out trophoblastic destruction so we reduce the NK cells when we see that they are elevated.

A lot of these patients with autoimmune disease and some of the newer therapies that we are using we spoke about the elevation of these inflammatory cytokines and the inability for those antigen presenting cells to remain in their tolerant state. I think this is one of the key problems in most of these autoimmune syndromes. One of the newer drugs we are using today is G-CSF, or Neupogen is the brand name and we know that Neupogen pushes these dendritic cells into their tolerant state. When we use this consistently throughout the first trimester as well as treating these other flammatory areas that we find, elevated NK cells, elevated T-cells we look at about 100 different data points and we treat them as they change. What we found is when we reduce these activity levels our pregnancy rates go up.

As an example, for women under 35 years old and the Sart statistics came out and we looked at our center, we treat, through the Sart statistics you can actually look to see how many previous IVF cycles have patients done before they did the cycle with you. We are typically triple the national average as far as how many patients have had previous cycles before we treat them. But our success rate this year was in the top five percent of the country. We know it is working.

Dr. Mettler: IVF success rates?

Dr. Braverman: Yes, and this does not take into account the patients we do not do IVF on, the patients who we consult with from other centers around the world. But here is the problem also, and this is the problem I spoke about earlier, it is no different than a kidney transplant. I think these have to be done at specialized centers where people truly understand immunology. A lot of people who order the tests, and I agree with you that they are very expensive, but they do not really understand what they are looking at and they just give impaired treatments, and many times they work. Many times patients get the correct treatment for the wrong reason. When they get failures they do not have a way of analyzing it. We have a long way to go. We are still trying to identify all the site of attack of the antibodies, the site of the attack of the T-cells. We have a pretty good handle on it, we know what to look for and what to treat. It is new and it is evolving but there is no question that we have improved the outcomes of many patients that otherwise had no chance to conceive at all.

Audience Member: A very brief question. Dr. _______ Staten Island, New, York. This question about, for Dr. Braverman, about what did you find and decided endometriosis when you did do laparoscopy, what were your findings? The reason I am asking is if it is silent obviously the findings themselves must have been very low. That is my suspicion.

Dr. Braverman: Actually, that is not what we found and that is what is interesting. We have many cases of stage four endometriosis without a single symptom and one of them that Dr. Seckin operated needed a bowel resection. Her only symptom was previous poor embryo quality. We actually did genetic studies on her embryos and they were all abnormal. We did the surgery. We tested her embryos. We finally had normal genetic embryos and the very first cycle after the surgery. we waited a few months, she got pregnant with twins and is close to delivering.

We see from mild to severe. One of the things I am looking at now is there any difference immunologically between these patients with silent endometriosis and those with pain? I do not think I will find it but I have not really seen a tremendous correlation between whether they have severe endometriosis or mild and all of them when they have had the surgery we have seen improvements in their outcomes.

Dr. Mettler: If you do not see any difference between the patient's endometriosis and no endometriosis immunologically what is all your immune therapy for then? Because you said it is for the endometriosis patients specifically and now you say there is no difference between patients with endometriosis or no endometriosis.

Dr. Braverman: What I am saying is that the immunological makeup of these patients with endometriosis and the functioning of the HLA molecules that are on the surface of their antigen presenting cells and in a patient with endometriosis most of those HLA molecules are in the autoimmune haplotypes. When they function sometimes they do not create tolerance. They allow for T-cells activation when it should not happen. They allow for antibody production during pregnancy when it should not happen. Whether they are mild or severe they all still have these autoimmune haplotypes, and just like women, some have the haplotype and never get autoimmune disease at all. But the functioning of those cells can be altered and the messenger presenting cells, these antigen presenting cells I think are the key. And that is our feeling. We have not...

Dr. Seckin: Can I just make this comment? I will not talk much...I am not supposed to talk...but this is very important. I personally, having done these very extensive cases, I never focused on this concept of silent endometriosis and I did not register that. I thought there will be some symptoms patients will always deny. But I have seen these patients and most of these patients are controlled, I have operated on. I was amazed to see very advanced endometriosis with no symptoms including that bowel resection patient. We have done many failed IVFs. The bottom line is we are clueless, clueless, even in clinical practice when we examine the patient how advanced the endometriosis could be.

In other words, deep endometriosis does not mean stage four endometriosis, or stage four endometriosis does not mean deep endometriosis. There is a different concept of this. So the ovaries could be involved high above but sonogram wise we can find things that pelvic exam a lot of times may be missed easily in the office because their cul-de-sac could be free by looking. It is not the same thing as looking by laparoscopy. I am sure many surgeons would agree with that.

Dr. Gomel: I concur totally. Endometriosis is a crazy disease. You have a patient with a few spots with a lot of pain and you have patients full of endometriosis and no pain. Now, the question is do you see a difference in those who have pain and those who have no pain.

Dr. Braverman: And the answer is no because remember what I am treating is the immunological condition associated with endometriosis. Endometriosis is just another symptom. What we feel is it is the HLA haplotypes of these patients that dictate their success in pregnancy. It is these HLA haplotypes that dictate how these antigen presenting cells are going to present paternal antigen and dictate whether they are going to get the normal level of T-regulator cells and dictate whether they are going to get antibody production during the pregnancy. To me, I do not see the association between the severity except obviously when it is more severe the tubes are not going to function they will probably be needing IVF.

Dr. Gomel: The question was if the patient has pain and a lot of endometriosis and another one does not have pain but an equal amount of endometriosis do you find any difference in their cytokines or something like this?

Dr. Braverman: I have not looked at that. That is something we are looking at. This is what I brought up during my talk, exactly, agreed, agreed. And what we wanted to do was look to see is there a difference in this immune panel that we do in the patients with silent, and we have the data, I have to go through it.

Dr. Gomel: That, I think, would be very interesting.

Dr. Braverman: I agree completely. We were looking at this just anecdotally when we were putting this talk together. We did not see it but we have not gone through all the data. It is a very good question, I agree with you.

Lone Hummelshøj: We have a comment from Dr. Cook and then one more question. Then we are going to wrap up this session and press on.

Dr. Cook: Dr. Braverman, great talk. I think you are really on the right direction of a little bit of what you guys were talking about the pain and fertility. We all know that the staging system does not predict fertility. But you know the work by David Adamson published in 2010 with the endometriosis fertility index was the first evidenced-based system that has been validated prospectively now for different studies in incontinence. Its ability to predict pregnancy following surgery prior to IVF and its scoring system where there are ten different levels and so the question follows thus, is the surgery helping with those immune factors? Is that how we are enhancing prognostic of the fertility and so using a scoring system it does predict and there is an algorithm that David is presenting at the World Congress in Brazil next month that he worked out. Question two is do they need IVF right away and based on the scoring system that is ___ what is their chance of fecundity with that idea? Just fascinating subject I could talk all afternoon.

Dr. Braverman: The answer is many do not go to IVF. Many get pregnant on their own. The first thing I ask the surgeons afterward is how do the tubes look. I think, when we look at endometriosis and infertility and we look at the issues of egg quality, we look at the issue of tubal motility, we look at these high levels of ROS that can attach to the sperm and prevent fertilization, if you debulk endometriosis and you also treat them with anti-inflammatory agents that lower these ROS levels I have a lot of patients who come back they do not want IVF and they come back spontaneously pregnant. It may take six months but it never surprises me when that happens. I think that a lot of our focus for those patients and - listen a lot of patients do IVF and they have been trying and they just want to get pregnant right away. But there is no question in my mind, although probably a little bit more difficult, but if we debulk them and we reduce the inflammatory response, a lot of them get pregnant without IVF.

Audience Member: I was thinking of how to form this question, how often do, should the women get checked for their autoimmune disorders? I myself had to have a total hysterectomy with both ovaries removed. It was not until after that happened that I was diagnosed with Hashimoto's and my latest blood work showed thyroid antibodies and I guess I am just wondering like I was really kind of freaked out by that and it just feels like this is never going to end. It is really expensive and confusing and you feel often passed around from doctor to doctor. I guess my question is how is a patient supposed to look out for themselves and to know how often they should be checked for these other autoimmune diseases?

Dr. Braverman: These are good questions. I am not a rheumatologist but one of the things that I have found...for you it would be a thyroid specialist and they would take care of this but the issue that we found, and again we stumbled into this, as we began doing these really expansive immunology profiles - and I do apologize another expense but we are working on that, I am working on that; we are lowering the prices and it is not me it is the laboratories, and I am yelling at them to get the prices down - but we need the information for this reason, here is one of the things that we found. Nobody looked at the serum cytokines in all these patients and we look at about 35 of them. They are such classic profiles that come in. We look at the haplotypes. I ___ look at the haplotypes which autoimmune diseases these patients are predisposed to and look at the serum cytokines and we are absolutely diagnosing these patients well before they are every going to show up at the rheumatologist or anybody else. And the literature shows this that you have pre-autoimmune disease. One of the most common ones we find is rheumatory arthritis, they have this inflammatory cascade, they have these elevations in the T-cells. Sure enough, we start doing the anti-CCP they come with strongly positive. They go to the rheumatologist, "You have no symptoms, you don't have anything'. But we know they are predisposed. In fact, many pregnancies that have TH2 dominant effects such as scleroderma get triggered during pregnancy. Pregnancy being a TH2 state we see the progression. Literature has shown that these women develop autoimmune disease based on their HLA haplotypes after a TH2 response to a pregnancy. We know that other autoimmune diseases that have cellular ______ get ameliorated by pregnancy. But we see these haplotypes, we see the Hashimoto's develop on endometriosis patients all the time and many other autoimmune diseases that come up during the infertility workups because what I said earlier is that one of the first symptoms of autoimmune disease are not the symptoms you are getting, it is infertility. Because the foreign antigen reacts with these HLAs in a much stronger fashion than self-antigen. It takes a much longer time for self-antigen to develop the response. I am getting the hand wave so I will stop.

Lone Hummelshøj: Thank you very much indeed. This was a very interesting discussion. We are going to press on now.