The DABBEC Phenotyping System

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webslave
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The DABBEC Phenotyping System

Post by webslave »

Nat Rev Urol. 2011 Feb;8(2):107-13. Epub 2011 Jan 18.
The DABBEC Phenotyping System: towards a mechanistic understanding of CP/CPPS.

Allsop SA, Erstad DJ, Brook K, Bhai SF, Cohen JM, Dimitrakoff JD.
Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.


There is an urgent need to elucidate the mechanistic basis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), as the current methods of symptom-based diagnosis and treatment have failed. Here, we propose a phenotyping system that bridges the gap between the symptom-based diagnosis and treatment of the present and the mechanistic approach of the future. Our phenotyping system uses the Chronic Prostatitis Collaborative Research Network (CPCRN)-recommended algorithm in combination with the NIH Chronic Prostatitis Symptom Index (NIH-CPSI) as a basis for diagnosis, while incorporating novel domains for quantitative assessment and stratification of CP/CPPS patients. We believe this novel system will serve to help advance our understanding of the roles of the patient's genome and proteome in the etiology of CP/CPPS. We predict that, as we begin to understand the mechanistic basis of CP/CPPS pathology and progression, we will develop specific treatments that will aim to cure the disease, rather than merely quell the symptoms.

PMID: 21243018 [PubMed - in process]

I'm trying to access the full text.

There is this box from the article —
In the UPOINT system, one of the designated domains is “tenderness of skeletal muscles”. While tenderness in the skeletal muscles is an important clinical distinction in CP/CPPS, it is a symptom that represents the final common pathway for numerous possible mechanisms (e.g. inflammation, infection, autoimmunity, nerve and muscle injury). The UPOINT system categorizes CP/CPPS patients with this symptom of muscle tenderness into a single mechanistic domain.

Contrarily, the DPS categorizes patients in a manner that does not rely on different symptom domains. Taking the initial symptom—tenderness of skeletal muscles—the DPS attempts to dissect the underlying mechanisms that shape the symptom perception. In addition, DPS provides a phenotypic framework that can drive clinical research focused on the mechanisms leading to the presentation of these different symptoms and provide a basis for adequate treatment.
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Re: The DABBEC Phenotyping System

Post by webslave »

I now have the paper, but cannot release the contents for quite a while. It's an interesting paper that I'm going to re-read and then I'll post a few select quotes.
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Re: The DABBEC Phenotyping System

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Has anyone got access to Nature Urology online here? If so, we can paste and discuss this extremely interesting paper, one of the most colorful in years.
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Re: The DABBEC Phenotyping System

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I want to go slowly over this paper over the next few weeks, discussing some key issues. I welcome your participation and comments.

Let's start. I'll highlight key concepts in red.
The single clinical entity known as CP/ CPPS is, in reality, a heterogeneous condition, both in terms of its clinical manifestations and its underlying mechanisms. At least three lines of evidence highlight this heterogeneity in CP/CPPS. First, the clinical presentation varies between patients and, even in the same patient, symptoms fluctuate over time.5 Second, different etiological mechanisms (such as infection, inflammation and nerve damage) might account for the observed pathology in the same patient and between patients.6 This presents a major challenge in defining the pathophysiology of CP/CPPS, which in turn presents a unique challenge in diagnosis and treatment. Finally, CP/CPPS symptoms overlap with those of irritable bowel syndrome (IBS), fibromyalgia, chronic fatigue syndrome, and other chronic pain disorders.7 The combination of these three factors creates considerable complexity in administering effective therapies for the alleviation of CP/CPPS symptoms.

5. Propert, K. J. et al. Design of a multicenter randomized clinical trial for chronic prostatitis/ chronic pelvic pain syndrome. Urology 59, 870–876 (2002).
6. Pontari, M. A. & Ruggieri, M. R. Mechanisms in prostatitis/chronic pelvic pain syndrome. J. Urol. 172, 839–845 (2004).
7. Rodriguez, M. A. et al. Evidence for overlap between urological and nonurological unexplained clinical conditions. J. Urol. 182, 2123–2131 (2009).
This highlights an area I've always found problematic, namely the claim that CP/CPPS is actually many conditions, or a condition with many different "underlying mechanisms".

I fully concede that the disorder has many faces, and that patients present in many ways. We see it here every day.

I also concede that the condition can be provoked by a number of different initiators, like stress + tensing of the regional musculature (which also occurs to confinement-stressed felines, resulting in IC, a factor this paper seems to ignore, preferring to focus on the stress + HPA axis aspects), infection, trauma (specifically trauma to spine or nerves related to pudendal nerve, although only proven in cases where viral infection has damaged a regional nerve branch). I do not accept that autoimmunity is an initiator (this paper does). I think the evidence for that is weak.

What I find much more problematic, because I think there is no real evidence for it, is that after the initiator, there are different underlying mechanisms. No, I see the initiators dovetailing into a common pathway, and that pathway is a complex combination of neuronal windup, allodynia, regional neuropathy, regional inflammation, self-reinforcing feedbacks, CNS complicity, muscular trigger points (common, but not universal). The usual initiator is stress.

Now remember, I am not a researcher, just an opinionated layman with a good grasp of the topic, so let's see it this hypothesis of mine stacks up against the full contents of the paper.

I will say this: Dr Dimitrakov does bring some new terms and insights into the condition in this paper, and you will all enjoy discovering them as we go along. I know I did :smile:
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Re: The DABBEC Phenotyping System

Post by carld »

Fantastic! I always said this is a constellation of issues that bring the initial onset. The main factors are rooted in stress, genetics ( and how we handle stress based on our gene pool) and diet...can't wait to read Dr. D's take...
I am not a medical doctor. Please fill out your signature (click here) ☼ ☼ My Starter List for new members
I encourage anxiety prone UCPPS people to consider L-Theanine
Age, 44 onset age 37 Feb 2006 Freq. need to urinate. Sensation of having to urinate soon after going. Perineum discomfort/burning/tightness, pubic area discomfort @ times,poor urine stream, post urine dripping/spray. All symptoms have improved with my protocol. At the worst I give it a 1 to 2 on irritation and discomfort and frequency. Helps: Elavil 5mg for anxiety and mast cell protection, (will only take it as needed) self internal PT as needed, stretching, walking, stairmaster cardio workout and light weights, reducing stress, moment to moment relaxation, deep breathing relaxation and using a Theracane. Makes worse: sitting for long periods, stress, over focusing on it. Currently 95%-98% recovered. Stay positive, relaxed and control your anxiety.
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Re: The DABBEC Phenotyping System

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BTW, just a glossary note:
  • "DABBEC" — stands for the authors of the phenotyping system (Dimitrakoff, Allsop, Brook, Bhai, Erstad, Cohen).
  • "DPS" — Dabbec Phenotyping System
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Re: The DABBEC Phenotyping System

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Next quote (color highlights added by me for critical discussion to follow):
The purpose of this article is threefold: first, we critically review existing knowledge on the diagnosis of CP/CPPS and propose our original phenotyping system; second, we evaluate several key contributing factors in CP/CPPS and propose a mechanistic roadmap for diagnosing and treating this condition; and third, we discuss existing obstacles in the design of clinical trials in CP/CPPS, and propose two novel study designs that we believe should be applied in the future.

Evaluation of CP/CPPS diagnosis

The NIH-CPSI

In light of the increasing perception of CP/CPPS as a symptom-based diagnosis of exclusion, in 1999 the NIH/NIDDK sponsored the Chronic Prostatitis Collaborative Research Network (CPCRN), which developed the NIH Chronic Prostatitis Symptom Index (NIH-CPSI ).8 The NIH-CPSI is a psychometrically validated index of symptoms and quality of life impact in men with CP/CPPS. The NIH-CPSI serves as the current criterion standard for the diagnosis of CP/CPPS, while providing a standardized outcome measure for CP/CPPS treatment efficacy.

Subsequently, the CPCRN used the NIHCPSI to evaluate the efficacy and safety of antibiotics9 and a-blockers,10 two commonly prescribed groups of medications in patients with CP/CPPS. Neither of the therapies was shown to be superior to placebo—an observation that could be explained by patient selection, a lack of clarity over optimal dosing, and the short duration of therapy.

However, it is also plausible that the outcomes of these randomized controlled trials reflect the fact that, while the NIH-CPSI captures a wide spectrum of clinical manifestations of CP/CPPS, it does not provide detailed mechanistic information. For example, two patients may present clinically with identical symptoms of chronic pelvic pain and be diagnosed with CP/CPPS on the basis of the NIH-CPSI . In the first patient, the pain could result from local inflammation caused by prostate infection, autoimmunity, or physical trauma. In the second patient, the pain might result either from a decreased pain threshold of the peripheral sensory nerve endings or from amplification of the pain perception within the central nervous system (CNS), known as central sensitization. Although the causative factors and pathogenetic mechanisms underlying the symptom (pain) in these two patients are quite different, they would be indistinguishable on the basis of the NIH-CPSI . Thus, although the NIH-CPSI allows the right patients to be captured (ensuring homogeneity), enrolling patients in clinical trials purely on the basis of their NIH-CPSI status might introduce even more heterogeneity to the study population. Theoretically, in the above example, even though the first patient would benefit from local therapies, the second patient would be more likely to respond to centrally acting analgesics.

8. Litwin, M. S. et al. The National Institutes of Health chronic prostatitis symptom index: development and validation of a new outcome measure. Chronic Prostatitis Collaborative Research Network. J. Urol. 162, 369–375 (1999).
9. Alexander, R. B. et al. Ciprofloxacin or tamsulosin in men with chronic prostatitis/ chronic pelvic pain syndrome: a randomized, double-blind trial. Ann. Intern. Med. 141, 581–589 (2004).
10. Nickel, J. C. et al. Alfuzosin and symptoms of chronic prostatitis-chronic pelvic pain syndrome. N. Engl. J. Med. 359, 2663–2673 (2008).
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Re: The DABBEC Phenotyping System

Post by critthinker »

Webslave, if you have the paper why can't you post the contents? I have the full article. How do I attach the PDF here?
Age: 27 | Onset Age: 26 | Symptoms: Pelvic pain (began w/ introduction into bladder/prostate of highly resistant strain of bacteria that was acquired via a Botox injection intended to treat levator ani syndrome) | Helped By: Paxil for anxiety, Trigger point release and trigger point injections, stretches, hot baths, Prosta-Q | Worsened By: Stress/anxiety, Sitting down for long periods,
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Re: The DABBEC Phenotyping System

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critthinker wrote:Webslave, if you have the paper why can't you post the contents? I have the full article. How do I attach the PDF here?
Please email it to me, thanks :smile:
webmaster at ucpps.men
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Re: The DABBEC Phenotyping System

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Continuing with my comments (others are welcome to join in):

"...an observation that could be explained by patient selection, a lack of clarity over optimal dosing, and the short duration of therapy."

Notice use of "could" rather than "is". Dr Jordan Dimitrakov (JD) et al are making a tentative suggestion here, not a statement of fact. And that's as it should be, because the idea that patient selection on the basis of different etiology (rather than symptoms) will make a huge difference to outcomes is not well supported in the literature. It's an appealing idea, you know, the concept that this difficult-to-treat bunch of men who present with pelvic pain and are seemingly unresponsive to almost all treatments can be transformed into a group that is much easier to treat, if only you can subdivide them according to (as yet unproven) etiological subclasses.

...prostate infection, autoimmunity, or physical trauma."

Past infection is a proven trigger, but this paper confusingly does not make it clear that the infection is an initiator of the condition, not an ongoing, active cause that must be treated with antibiotics. That is either and oversight, an error, or a deliberate and clever attempt to appeal to the doctors who still adhere, at some level, the the archaic ideas of infection that still swirl around the condition, especially doctors who are not up to date with current research. So it could be diplomacy rather than science. However, the other issue I have with this is that it is presented as representing a different underlying mechanism, and that's where I cannot see any evidence. In my view and according to much anecdotal evidence we've all seen in these forums (and it's backed up by an excellent 2011 study by Schaeffer et al), a past infection can start up the typical cycle of CPPS, and does not represent a unique mechanism that would indicate a unique treatment at all.

Autoimmunity? Where's the proof for that? The main researcher pushing this theory, Richard Alexander, could not show statistical difference between CPPS patients and normal men when measuring autoimmune reactions to prostate proteins ("The recognition of prostate specific antigen peptides was not statistically different when comparing cases to normal male blood donors individually" - abstract) So why even reference autoimmunity as an underlying cause? If this were an autoimmune condition, we should see some real prostate organ damage, but we don't.

Physical trauma: what kind of physical trauma? Where are the studies that prove physical trauma causes CPPS? It's true that we have seen anecdotal cases where people who have lower or lumbar spinal problems also develop chronic pelvic pain syndrome, probably because of nerve crosstalk, and we have seen women who have had spinal injuries, for instance in a car crash, then go on to develop IC, but where are the studies backing the anecdotes? I do think that any insult to the region can set up a neuromuscular guarding response that then may cascade, in genetically and psychologically susceptible individuals, into CPPS (or IC), but the literature is non-existent and I'm basing this on case histories.

I hope members of the forum can now see some of the problems with the paper (it also has strengths; we'll get to them later).

"the pain might result either from a decreased pain threshold of the peripheral sensory nerve endings or from amplification of the pain perception within the central nervous system (CNS), known as central sensitization"


And here, for me, is one of the paper's strengths. I think this "underlying mechanism" is a factor in all cases. It's an unmeasurable quantum (I stand open to correction on this) as far as I know, so nobody can say for sure that it's only a factor in some cases. Without the ability to make that distinction, and using Occam's Razor, I say it is a factor in all cases.

In fairness, JD does propose a way to measure this aspect later in the paper: the Lidocaine Test as used in PBS/IC patients. This test would utilize a lidocaine cream to numb the urethra and the urethral part of the prostate. He says "Persistence of pain (negative outcome) would suggest a central pain syndrome." (I need to note that we had a patient of JD's, who had a cream inserted in his urethra, report that he was permanently affected by the procedure in a negative way.) Whether this test would be able to make a distinction between patients with and without CNS involvement is moot. It's an interesting idea, that's all, at this stage.

However, I like the way this paper brings the CNS factor into the fore. The UPOINT system (PDF of study) also mentions this factor:
...central and peripheral neurologic changes (allodynia, hyperalgesia), and psychosocial changes that can maintain the clinical syndrome years after the initiating injury has resolved.
The abovementioned quote was cited by Shoskes to the Pontari study that concluded that CPPS results "from an interplay between psychological factors and dysfunction in the immune, neurological and endocrine systems", which with I'd agree, although I'd add "neuromuscular" to that definition.

"Although the causative factors and pathogenetic mechanisms underlying the symptom (pain) in these two patients are quite different"

I don't think that's been proved at all, and I have to disagree with it.

General comment: these PHENOTYPING systems, (UPOINT and now DABBEC) have arisen because researchers have found no biomarkers to help guide classification and treatment for the condition. But the attempt to phenotype patients is clearly fraught with pitfalls and problems.

At this stage, I think phenotyping systems may be useful in choosing treatments, but not at identifying underlying mechanisms. So yes, by all means classify patients according to symptoms and treat different symptom clusters differently, but do not make the leap to linking symptoms with hypothetical etiology. An example of how classification should be used is given by Shoskes in his paper CPPS: The Status Quo Is Not Good Enough (But It Can Be)
D Shoskes wrote:Learn and use simple and effective therapies for the
different clinical domains:
• Urinary symptoms: alpha blockers or antimuscarinics
• Prostate pain or inflammation: quercetin and
cernilton
• Systemic neurologic symptoms: pregabalin or
amitriptyline
• Pelvic floor spasm: pelvic floor physical therapy
(myofascial release, NOT Kegel’s)
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Re: The DABBEC Phenotyping System

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I notice that the full paper is now available here:
http://www.ucpps.men/1/
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Re: The DABBEC Phenotyping System

Post by gmccormack »

Any idea how many phenotypes exist? I agree with Dimitrakov that the condition changes over time, this makes the number of phenotypes practically endless. You could have patient A with urethral burning in 2006 - phenotype A, then in 2008 have testicle soreness - phenotype B, because the patient has had both now moves to phenotype AB. Obviously this is not a live example, but not even getting into proteomic, genetic, and other lab tests there could be thousands. I agree with the theory of phenotyping and will go further than webslave and say it is way to determine etiology if you test enough patients. Take for example breast cancer, science used proteomics and tested hundreds of thousands of patients and eventually found the proteins responsible, so that would mean they found the etiology of the disease. In CPPS case this would be one phenotype.

In terms of central pain disorder test, it makes sense. If pain persists after lidocaine then obviously the CNS is playing a role. How do you solve that problem? Answer is you don't, Lyrica and others like it show 15% respond in off label neuropathic pain disorders. Central sensitization/ cross sensitization/ neuronal windup/ CNS plasticity the list goes on, we know it exists and maybe with phenotyping we can show evidence of it in CPPS but what do we do with that? Anti NMDA receptors are not commonly used in pain clinics because they don't show effectiveness other than anecdotal.

Another question I have is that studies have shown that 80% (brewer et al) of men have resolution of symptoms within 5 years, Dimitrakov has said this before as well, and number of men here have had that occur on this board. What happens to the underlying mechanism? It just fades away? If it fades away, what is the cause of it fading away?

On a more trivial note, why was lidocaine cream put into the urethra why not inject it with the liquid form seems much less messy and less likley to cause problems as the one patient Webslave mentions?

Personally, I believe that CPPS patients in our lifetime will get more out of advancing pain medications, a cure is just too hard to believe in.
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