Large datasets shed light on benign urologic conditions

Large research initiatives such as the MAPP (Multidisciplinary Approach to Chronic Pelvic Pain) Research Network and LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) seek greater understanding of conditions including urologic chronic pelvic pain syndrome, LUTS, nocturia, and more. In this interview, J. Quentin Clemens, MD, who is a researcher for both networks, discusses the research conducted by these groups and what practicing urologists can learn from their findings. Dr. Clemens is professor of urology and chief of neurourology & pelvic reconstruction and director of the female pelvic medicine and reconstructive surgery fellowship at the University of Michigan, Ann Arbor.

Dr. Clemens was interviewed by Urology Times Editorial Consultant Gopal H. Badlani, MD, professor of urology at Wake Forest Baptist Medical Center, Winston-Salem, NC.

Please discuss the MAPP Research Network and the work it is doing.

Both the MAPP (Multidisciplinary Approach to Chronic Pelvic Pain) Research Network and the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) are funded by the National Institute of Diabetes and Digestive and Kidney Diseases. The NIDDK leadership identified a need for research groups to get together and study certain benign urologic conditions. The MAPP is focused on urologic pain conditions, which we’ve termed urologic chronic pelvic pain syndrome or UCPPS, and which refers to interstitial cystitis, bladder pain syndrome, and chronic prostatitis/chronic pelvic pain syndrome. It’s a six-site network that has essentially conducted cohort studies of these patients and a lot of very interesting analyses to try to better understand important subgroups.

Some of this work has involved looking at clinical data. For instance, we’ve identified that pain and urinary symptoms really are different concepts in that certain patients have more pain and certain patients have more urinary symptoms. Those don’t track very well together at all, either at baseline or longitudinally, so it suggests that there are two subgroups: pain patients and urinary symptom patients.

We see that clinically: You have some patients who urinate every 15 minutes, but they don’t say they have pain, and you have others who might have a lot of pain, but they may not urinate as frequently. We think that’s important because it will help us focus research on which treatments might improve which type of symptoms.

We’ve also done a lot of studies looking at neural imaging and experimental pain testing that have demonstrated that many patients have objective abnormalities, which is unique for pain syndromes in urology. This type of thing has been shown in other pain syndromes. But many patients have a centralized phenotype. In other words, they have not just pain in the pelvis but pain elsewhere in the body and hypersensitivity.

Is it fair to say that there are bladder-centric and non-bladder-centric pain syndromes?

I think so. The next step is to see how important this is. For instance, do certain types of patients respond better to certain therapies? That would tend to finalize the story that, yes, there are two different types of patients that we should treat differently.

Next:The LURN networkPlease tell me about the LURN network.

In some ways, the LURN has a more ambitious goal because it is studying a broader range of symptoms-essentially all of the non-painful urinary symptoms, so LUTS, overactive bladder, incontinence, etc. What that network has focused on is gathering baseline data, including a large volume of clinical data as well as post-void residual volumes, urinalyses, and physical exam data. Then, it uses complicated, state-of-the-art statistical methods to identify clusters of individual patients and compare those clusters to our traditional clinical phenotyping.

We’re finding differences and we’re not sure exactly what that means at this point, but the concept is that by using these computer techniques, we may be able to gain insight into differences in patients, which will in turn will give us insight into how to treat them differently.

Please discuss what was gleaned from the LURN in regards to nocturia.

We collected 3-day voiding diaries on all 1,000 patients, so we have a huge amount of data that we can analyze related to the diaries as well as bother. Most studies suggest that nocturia times one is not very bothersome to patients. But in fact in the LURN, which is a group of care-seeking individuals, nocturia times one was very bothersome. We should not ignore that, and many of the patients come to see us for that.

We’re just starting to look in depth at the various subtypes of nocturia, and we see a lot of nocturnal polyuria and a lot of mixed patients as well. We’re starting to look at correlates of what predicts certain types of nocturia in both men and women, which we don’t have the data yet to look at.

We are following the patients out for a year, so we’ll be able to take the baseline data and see how that correlates with treatment response. There are different treatments that are prescribed by the LURN clinicians.

What did you learn regarding male symptoms?

One potentially very important observation is the high rate of urinary incontinence that is reported. This is not just post-void dribbling; it seems like there’s a pretty high rate of urge incontinence as well. That’s a type of symptom that really is not assessed at all on the AUA Symptom Score, and our results suggest that it’s a more bothersome and prevalent symptom in men than what we might have otherwise thought.

Did the LURN come up with a new symptom score to address this?

Yes. The first step has been to develop a very large, comprehensive symptom questionnaire that is not meant for clinical use. This is to identify potentially important subgroups and be very detailed in how the questions are done. However, we have done analysis of that and have come up with a shorter version that we are testing, and the plan is to have an instrument that is short but comprehensive that could potentially replace some of the existing instruments we have such as, possibly, the AUA Symptom Score.

How about the female side? Any new caveats regarding female LUTS for practitioners to use?

The clustering analyses that we have done have focused a little more on women than men so far. What’s interesting is there’s a very severely impacted group that has a wide range of symptoms and seems to have a wide range of psychosocial abnormalities and other abnormalities as well. What that suggests is perhaps along the lines of some of the pain patients we see where there may be more of a need for multidisciplinary management of certain patients than others. So, again, this is very preliminary, but I think some very exciting new concepts will emerge related to female LUTS along those lines.

Next:Polypropylene mesh has been used in men for hernia repair for so long; why is it only controversial in females?Switching gears a little, mesh has been in the news a lot in recent years. Polypropylene mesh has been used in men for hernia repair for so long; why is it only controversial in females?

What’s interesting is it actually is somewhat controversial in men. There’s a fair bit of research in the general surgery literature that raises the question of not just pain but potential for systemic effects of the mesh similar to what’s been concerning in women. The FDA warning came out for female mesh and that has really highlighted a lot of the controversy and news about it, but there are questions about male mesh as well.

Also see: Nocturia treatment efficacious after single dose

I was involved in research that looked at the New York state database and compared mesh patients with controls (Am J Obstet Gynecol 2017; 216: 495.e1-495.e7; Hernia 2017; 21:637-42; J Urol 2017; 198:884-9; Am J Surg 2018; 216:481-6). We looked at men who had mesh for hernia repairs and women who had mesh for prolapse. We followed these patients out for 5-6 years and looked for the development of conditions like cancers and autoimmune diseases.

There was absolutely no effect. In fact, in some of the analyses, the mesh was protective, which of course is just a statistical thing. But the concept here is that there certainly can be local complications associated with mesh placement (pain, infection), but there is currently no compelling clinical evidence to support that mesh implantation causes systemic complication such as autoimmune disease or cancer. That’s an important message because we need to focus on where the problem is and where the problem isn’t.

Evidence from a large dataset show an exposure rate of 3% to 10% in patients undergoing mesh placement without hysterectomy (Int J Womens Health 2015; 7:331-43), but other factors could be involved, such as how the mesh is placed, the product versus the procedure, etc. Are we giving up on a good thing for a problem in a few?

I get your point and to some degree I agree in the sense that most people feel there probably is a place for mesh, but right now it’s not been well determined what that place is. There are registries. For instance, there’s a registry that the American Urogynecologic Society has put together working with the FDA to try to answer some of those questions.

Read: Botulinum toxin more cost-effective than SNM

I think the real concern is the possibility that mesh slings will be abandoned. The FDA warning specifically indicated that it was not referring to mesh slings, but rather was focusing on "mesh kits" for the treatment of pelvic prolapse. I think the data indicates that, compared to the alternative, which are autologous slings, mesh slings are less morbid and for most patients equally effective.