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Dr. John Warren - The Antiproliferative Protein

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  • Dr. John Warren - The Antiproliferative Protein

    Topic: An update of current IC research: the antiproliferative protein found in the urine of IC patients, antibiotics, heredity & IC.

    Speaker: Dr. John Warren, Director of the Interstitial Cystitis Center - Univ. of Maryland School of Medicine.
    Moderator: Jill Osborne, ICN Founder
    Date: October 12, 2000


    Jill Osborne - Greetings and welcome to the ICN Meet the Expert Chat for October 12, 2000. We are pleased to offer the only live (and free) chats on the web featuring prominent IC researchers and physicians. The ICN Meet the Expert chat series began in 1998 and has featured more than 28 IC moderated presentations.

    Tonight we welcome Dr. John Warren. Dr. Warren is a Professor of Medicine and the Director of the Interstitial Cystitis Center at the University of Maryland School of Medicine. The recipient of several prized NIDDK/NIH and ICA research grants, he has dedicated much of his career to the study of interstitial cystitis. The University of Maryland IC research studies are considered some of the most dynamic and promising in the US today, leading investigations into the isolation of the antiproliferative (APF) protein found in the urine of IC patients, the use of sequential antibiotics in treating IC and a variety of other studies. Dr. Warren is currently the Principle Investigator of the Maryland Interstitial Cystitis Clinical Trials Group. This is a rare opportunity to meet and hear from one of the most accomplished IC researchers today. Dr. Warren, welcome to the IC Network!

    <drwarren> I'm delighted to be here and look forward to the discussion.


    <icnmgrjill> How did you first become interested in IC?

    <drwarren> My training is in infectious disease and my research has been, for many years, urinary tract infections. Initially, we had wondered if IC would be the result of an unusual UTI but after a lot of arduous work by my colleague Dr. Susan Keay and others, we do not feel that IC is caused by an infectious agent.

    But, by that time, both Dr. Keay and myself had become interested in IC and had gotten to know a number of patients. We were looking for some ways to relieve the symptoms of IC and so we continued to look at the possible causes of IC in studies funded by the NIDDK and the ICA.

    As you suggested, I think the most exciting thing is Dr. Keay's isolation of a small peptide found in the urine of about 95% of IC patients. A peptide is a very small protein. This peptide is found in less than 10% of patients without IC but who do have a number of other urologic diseases. We've analyzed several hundred patients in these research groups.

    <icnmgrjill> Why do you think the peptide is present and where is it coming from?

    <drwarren> I'm not sure that I can answer the "why" but to our knowledge it is quite unusual in the sense that it inhibits the growth of bladder epithelial cells and is also produced by bladder epithelial cells of IC patients but not in normal controls. So, that's the "where." It doesn't come from other parts of the body through the kidney nor is it made in the kidney. It is made in the bladder by bladder epithelial cells.

    <icnmgrjill> So... is it possible then that you have found an identifying marker for IC that could be used in diagnostic tests.

    <drwarren> Yes. Dr. Deborah Erickson at Hershey has studied 16 different possible diagnostic tests for IC and this is the best of the group. She's been able to pick up more than 90% of IC patients and also exclude more than 90% of the patients who don't have IC. Our hope is that this will be a more widely available and easily used diagnostic test rather than a cystoscopy with hydrodistention

    <icnmgrjill> That's wonderful. We have patients who are reluctant to have the hydrodistention and it will be comforting for them to know that there will be some other options?

    <drwarren> We hope so.

    <icnmgrjill> Is it also possible that a treatment could be developed which turns off the protein and will allow bladder healing?

    <drwarren> Ultimately is our hope. We believe that the antiproliferative factor (APF) is important to the cause of IC so if we can find a way to inhibit its production then we should be able to develop some new treatment options

    <icnmgrjill> One of the recent papers that your team published related that for some patients percutaneous nerve stimulation "normalized" APF & growth factors. We find that very interesting... can you tell us more about that?

    <drwarren> This was work done by my colleagues Drs. Toby Chai and Susan Keay who found that two procedures, one the venerable hydrodistention and the other the stimulation of the sacral nerve, tended to normalize the antiproliferative factor in the urine as well as the growth factors. This work was funded in part by the ICA.

    <icnmgrjill> Can you explain what a growth factor is?

    <drwarren> A growth factor is a protein produced by cells in the body which acts to help those cells multiply and grow. If a cell gets a signal that it has to grow it will produce a growth factor that will then attach to the outside of the cell. This then begins the cell growth process. This research is very preliminary.

    <icnmgrjill> Let's move on to sequential antibiotics. Back in the IC dark ages, there was a group of individuals and physicians who believed that IC was caused by some type of bacteria. And, indeed, several doctors and researchers have worked to isolate a bacteria as you described in your intro. One of the earliest researchers was Dr. Durier (Canada) who released what he felt were positive results in treating IC with sequential antibiotics. But, I think.. and correct me if I'm wrong.. few other researchers, if any, have been able to duplicate his results.

    <drwarren> I'm not sure that anyone has tried other than us. The background for this is back in those dark ages. I wanted to find an infectious cause for IC so the way we went about this was a careful study of a small number of IC patients. We also studied patients who didn't have IC but were undergoing cystoscopy for other reasons.

    With a number of sophisticated techniques that looked for bacteria in the urine and other bladder tissues in both groups of patients, Dr. Keay and I found no organism in the control patients. In 6 of our IC patients, however, we found a variety of different species of bacteria many of which are not normally thought to cause disease.

    We tried to find some common thread among all of the bacteria that would explain the connection but were unable to. We then realized that the bacteria were probably the result of the IC rather than the cause of the IC.

    Let me explain this further. Women, with their short urethra, often have bacteria in their urine. 99% is normally washed out of the bladder during urination but the small number that remains in the film of urine that coats the bladder are then killed by the epithelial cells in the bladder. Because the epithelium in an ICer is damaged, we hypothesize that some bacteria can survive. They may not cause the disease of IC but they may be initiating a low level inflammatory response which may cause some of the symptoms of IC or an exacerbation (flare) of the IC. Our thought was that if we could clear the bacteria, that this could possibly improve their symptoms

    Through his work, Dr. Durier had the largest reported use of antimicrobials but that was only in abstract form and many of those patients did not have confirmed IC. We duplicated his regime and added a couple of additional broad-spectrum antibiotics that would kill a few other bacteria as well. So we had a very broad spectrum of antibiotics that would kill a very large spectrum of bacteria.

    Funded by the ICA and with antibiotics suppled by manufacturers, we used six antibiotics for three weeks each for a total of 18 weeks. We also gave weekly diflucan to prevent vaginitis. We randomly assigned patients to get the antibiotics or placebo and we calculated that if the antibiotics were 60% effective and the placebo 20% that we would need 44 patients in the study.

    Drs. Chai, Keay, I and our colleagues here recruited 50 patients and had 25 in each group. The study was double blinded so that neither we nor the patient knew if they were being given the medication or placebo. The results were that 48% of the patients receiving antibiotics had improvement of their IC symptoms compared to 24% of controls. 80% of the patients receiving the antibiotics had one or more side effects.

    At the end, most patients taking the antibiotics knew if they were taking antibiotics because of the side effects. What we know about the placebo response is that if you think you are getting an active therapy, you're more likely to respond it. So, if anything patients receiving antibiotics should have had a heightened response. If this were a larger study, and these figures held, then you could say that the antibiotics were better than placebo for IC.

    Our interest in pursuing the therapy was not satisfied by this relatively low response and so our feeling and recommendations are that antibiotics given this way, alone or in different combinations, may sometimes be associated with decreased symptoms in some patients. But, this does not represent a major advance in therapy for IC.

    I think that IC patients, more often than others, have bacteria that they are unable to get rid of so it certainly is reasonable for patient early in the disease (or during a flare) to have a urine culture done and to treat organisms even at low concentrations. Why? Because some patients may get relief. But the bottom line is that there is no evidence that we, nor anyone else, that IC is an infectious disease. Bacteria does not appear to cause IC but it could cause an exacerbation of the symptoms.

    <icnmgrjill> Some patients worry that they could pass IC onto to their sexual partners. Any comments?

    <drwarren> Two things that should put ones mind at ease. If IC was a sexually transmitted disease, it would be seen more frequently among women and men who have large numbers of sexual partners but the epidemiology that exists indicates that this is not the case.

    Secondly, we hope to be doing a study of risk factors for IC and will be looking specifically at the issue of possible sexual transmission. But, again, there is no evidence suggesting that.

    Finally, as part of our study of family history of IC, we'll be asking spouses of IC patients to give us their own family history of IC including whether their spouse has IC or not. If it were sexually transmitted, we'd expect it be higher in spouses.

    <icnmgrjill> Can you share with us a little bit more about your study of genetics and IC?

    <drwarren> At this point it's a study of the prevalence of IC found in families. Funded by the Fishbein Family Foundation, Drs. Jinfeng Xu, Deborah Meyers and I sent out a survey out through the ICA update and received 2500 responses. About 2000 have full family reports. In those, about 4% of IC patients report one or more first degree family members (children, parents, siblings) with confirmed. We developed preliminary family pedigrees, diagrams of families, and IC is present in some families for three generations and goes into second and third degree relatives (aunts, uncles, nieces, nephews and cousins). This is consistent with genetic transmission.

    Finally, a number of twins responded to our survey. We compared identical twins (those who share all the genes) with fraternal twins (those who share half the genes). In nine identical pairs of twins, 4 or 5 of the twins have IC. Of the 25 fraternal twins, none of the twins have IC. So, there does seem to be a genetic susceptibility to IC. This is like many other so called "complex" diseases like diabetes in that there are genes that make one susceptible to disease but then there also has to be one environmental condition that has to happen to trigger the disease.

    <icnmgrjill> Let's take some questions from the floor. The first question is from Joy. She wants to know if you ever isolated enterococcus from the bladders of IC patients and is enterococcus is bad to have in the bladder.

    <drwarren> In our study, we carefully obtained urine at the time of cystoscopy and no patient had enterococcus. Enterococcus, as you know, is an organism that lives in the colon and can be in the vagina and the periurethral area. It is also found around the urethra and the distal portion of the urethra.

    I'm aware that enterococcus has achieved some prominence among some members of the IC community. I think this is based mostly on urine specimens mailed through the post office.

    Let me first offer some background. Bacteria are naturally found on the perineum and in the outer portion of the urethra so one has to be very careful in collecting a urine specimen to clean the area. The initial portion of the urine may also have bacteria and that's why we ask for a "midstream" catch when we ask patients for urine samples.

    In a urine sample that is allowed to sit at room temperature for hours (or two days if sent by mail), even a small number of bacteria will multiply. Just one bacteria that has dropped into the urine from skin during collection will multiply and, after two days, will be present in hundreds of thousands.

    So, let me go ahead to what I said before. I think it's reasonable for someone early in diagnostic process to have a urine culture and if they have even small numbers of bacteria to be treated with antibiotics but I don't think it's a cause of IC. Rather it may be a result of IC. If a patient has an exacerbation of symptoms, it would also be reasonable to have a urine culture and to treat any organisms present.

    But that urine needs to be carefully collected, with a rigorous cleansing before hand. Rather than mailing your urine through the mail to a lab, it should be refrigerated as soon as it's collected and sent to a clinical lab quickly. These are widely accepted standardized routine procedures for collecting and processing urine.

    <icnmgrjill> This is from Bev, the Orange County ICA support group leader. Lots of studies have looked for bacteria in IC bladders and come up with nothing conclusive. Would it be reasonable (given that many IC patients had abdominal surgery prior to the IC's onset) to look at the outside of the bladder, at least in that subset of patients?

    <drwarren> That's an interesting question and there are two issues. One is about prior abdominal surgeries. It's unclear from the data available whether these surgeries precede or are done to try to identify the cause of pelvic pain. We hope that we can study that.

    <drwarren> But the more interesting question is whether it's outside of the bladder. The inside of the body (other than the GI tract) usually do not have bacteria but that doesn't mean that it couldn't have other types of organisms, such as viruses. To date there are no viruses that I'm aware of that infect a bladder wall. But it maybe that some day we will know more. That's an interesting question. Getting an answer is going to be the difficult part.

    <icnmgrjill> This is from Maria in Australia. Could the contraceptive Depo provera have any adverse affect on IC.

    <drwarren> Well, that's a good question but I'm not sure that there is a good answer. We know that many IC patients have changes in their symptoms around the time of their menstrual symptoms. We know that estrogen has an effect on mast cells. So, oral contraceptives conceivably could have an affect on IC. We intend to look at that in our case control study regarding contraceptive use prior to the onset of symptoms.

    <icnmgrjill> Bonnie asks "What is the evidence for ureaplasma, mycoplasma, and chlaymdia infections causing urinary urgency, frequency, and bladder pain?"

    <drwarren> That's another good question. In our study that I described earlier, we were looking for those organisms and did not find them. In a subsequent study using PCR testing, Dr. Keay sought and was unable to identify some of those organisms. A group at Vanderbilt has done half the study (they looked at IC patients but not controls) and reported a proportion that have chlamydia but that same group has been reporting that organism for a number of different diseases. I think it would be reasonable for other groups to try and confirm their findings.

    <icnmgrjill> What research do you feel is the most promising at this time? What are your colleagues excited about?

    <drwarren> I think among our research the two areas we are the most excited about is the the role of apf in the pathogenesis of IC particularly because of the ramifications on future treatment options.

    The second is the possibility that IC has a genetic susceptibility. The more we understand genetics, the more we understand the pathogenesis of the disease and the more ways we can inhibit the cause. If we can identify those at risk for the disease, we can possibly prevent the disease.

    For example, if a UTI can initiate IC, we can take measures to prevent UTIs such as nightly low dose antibiotics, antibiotics after sexual episodes just like we do to prevent recurrent UTIs. Once again, this is not saying that IC is an infectious disease. But just envision a patient has a factor in their urine that will prevent bladder repair. When that bladder is damaged (i.e. during infection), the bladder may be unable to regenerate or repair itself. So now you have a chronic damaged bladder that could be irritated by a number of factors: by bacteria, by toxins in the urine, by those exposed to allergens in the urine and the bladder itself. All of these things can lead to a low level inflammatory response.

    The third thing is if there is a genetic susceptibility. With all of the difficulties to gene therapy, one of the biggest barriers is getting the right gene to the right cells. With the bladder epithelium, we have with relative ease the ability to get the right gene to the right cell via bladder infusion.

    <icnmgrjill> Dr. Warren.. Do you feel that IC is an autoimmune disease?

    <drwarren> Dr. Keay has looked at this and we feel about this the same way we do about bacteria. In both cases, we think that these are result and not cause of IC. We and other people who have looked have found a wide variety of antibodies generally at low concentrations and which go up and down in concentration over time all of which is more consistent with bladder damage and exposure of the rest of the body to allergens within the urine and from inside the damaged epithelial cells. So we think that there are some autoimmune aspects, but these are likely the result and not the cause of IC.

    <icnmgrjill> Thank you so much Dr. Warren for sharing your time and your insights on IC with our online audience. You were great.

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