Tuesday, July 24, 2007

Treating Dupuytren's disease

There's some correlation between Peyronie's disease and Dupuytren's contracture, though the structures involved are fairly different. So this treatment for Dupuytren's, a disorder for which there's been no good treatment, is at least of passing interest:
Straightening Bent Fingers, No Surgery Required - New York Times

Keith Felcyn, a retired senior editor of BusinessWeek magazine who lives in Greenwich, Conn., had not been able to fully extend the little and ring fingers of his left hand for 20 years. But last month, it took 20 minutes for a doctor in Ontario, Ore., to reverse his Dupuytren’s disease, a benign but ultimately disabling disorder in which the fascia of the hand thickens and draws the fingers permanently into the palm.

The disabling disorder causes patients’ fingers to become fixed in a bent position.

“When he finished and I could lay my hand flat,” Mr. Felcyn recalled, “I said, ‘My God, this is a miracle.’ ”

The procedure, called needle aponeurotomy or percutaneous fasciotomy, involves using the bevel of a hypodermic needle to essentially shred the ropes of constricting fascia characteristic of Dupuytren’s disease. The disorder, named for Baron Guillaume Dupuytren, a 19th-century French surgeon who wrote about it, afflicts up to 25 percent of people over 40 in Western countries and is most common in men of northern European descent. Ronald Reagan had it; so does Margaret Thatcher. Risk factors for the disease include hand or wrist trauma, repetitive strain, alcoholism, smoking and diabetes.

Needle aponeurotomy, which leaves only superficial puncture wounds, was developed 30 years ago by a group of French rheumatologists and is now being practiced in the United States by fewer than a dozen physicians. Thousands of patients like Mr. Felcyn are flocking to these doctors every year, many against the advice of hand surgeons who say open hand surgery is more effective.

“Surgery has a lower recurrence rate,” said Dr. Richard Gelberman, chairman of the department of orthopedics at Washington University in St. Louis, and president of the American Society for Surgery of the Hand. The recurrence rate for needle aponeurotomy is around 50 percent after three years, according to several studies published in French medical journals. Studies in the British and American medical literature indicate that the recurrence rate for fasciectomy, or surgical removal of the diseased fascia, is 40 percent after five years.

But surgery carries a significantly higher risk of complications like nerve and vascular injury, infection, inflammation and something called a flare reaction in which the hand gets very swollen, red and stiff.

“Fasciectomy is a delicate procedure that requires meticulous technique,” said Dr. Steven Z. Glickel, director of the C.V. Starr Hand Surgery Center at St. Luke’s-Roosevelt Hospital Center in New York. Moreover, he added, “Patients have to be committed to physical therapy” for six weeks to four months before they can expect to regain full function of the hand.

Mr. Felcyn played tennis the day after his needle aponeurotomy, which, unlike surgery, can be easily repeated should he have a recurrence.

Dr. David Kline, who performed the procedure using a mild local anesthetic, had the same thing done to both his hands five years earlier in France.

“I cried the day I had it done,” Dr. Kline said. “I was so happy to be able to use my hands.” As an emergency room doctor, he had thought his career was over until an Internet search turned up a group of rheumatologists at the Hôpital Lariboisière in Paris offering an alternative to surgery.

Dr. Kline paid 40 euros, about $55, to undergo the procedure. He returned to Paris in 2005 to receive training in the technique. Dr. Kline said he had since performed more than 600 needle aponeurotomies, in addition to continuing to practice emergency medicine, at Holy Rosary Medical Center, in Ontario, Ore.

There is little competition because so few doctors offer it in the United States; a list can be found at http://www.dupuytren-online.info/needle-aponeurotomy.html.

The cost is $500 to $650 per affected finger and is covered by Medicare.

Dr. Charles Eaton, a hand surgeon in Jupiter, Fla., said the technique had been slow to gain acceptance by other American surgeons because “it sounds crazy to work on the delicate structures of the hand without cutting it open to see what you are doing,” especially when Dupuytren’s disease often distorts the anatomy of the hand.

But because patients are awake for the procedure, he said they can report a tingling sensation if the one-half millimeter needle gets too close to a nerve, and they can move their fingers to reveal the location of tendons.

“It took a long time for arthroscopy to take hold, too,” Dr. Eaton said.
It would be interesting to understand exactly how and why this works. I was surprised by the cited prevalence for Dupuytren's. If it's really that common (25%?! of all men over 40?) then any historic association with Peyronie's may be completely coincidental.

Update 8/4/07: The prevalence of contractures is not 25%. Amongst Caucasian European males over age 40 it's probably 1-4%, and maybe 5%+ in Scandinavians.

Friday, July 6, 2007

Proteomics in Peyronie's Disease - including a review of gene profiling in PD

This article isn't published yet, the abstract is from an electronic preprint:
Is There a Role for Proteomics in Peyronie's Disea...[J Sex Med. 2007] - PubMed Result

...This review assesses the potential use of protein alterations measured by various novel technologies, to predict progression, regression, or stabilization of PD in an affected individual. Methods. A comprehensive literature review of the past decade in the field of gene profiling and protein expression of PD was performed...
As I wrote a couple of days ago, even an area as understudied as Peyronie's can advance quickly when new instruments are brought to bear on old questions. Proteomics is all the rage in our post-genomic era, but besides the faddish topic the article claims to have reviewed the full literature on gene profiling in PD (of course that probably took about 3 hours).

This is one article I'm going to have to drag out of the university library -- once it's published!

Another 1960s article on Peyronie's and other "collagen" disorders

This French article from 1964 is the second I've come across discussion combinations of Peyronie's disordr with other disorders of fibrosis ("collagen" in those days): [A COLLAGEN TRIAD: LA PEYRONIE'S DISEASE, DUPUYTRE...[J Urol Nephrol (Paris). 1964]

It's an area of research that died out in the 1960s apparently.

The triad was "PEYRONIE'S DISEASE, DUPUYTREN'S DISEASE AND FIBROSIS OF THE AURICULAR CARTILAGE". I don't know the last, but for what it's worth I used to have odd lumps of fibrous material in my pinnae (soft tissue at base of the auricle) though they've since faded.

It would be interesting to get hold of one of these old, old articles ....

Peyronie's Disease: Type I and Type II?

I've been thinking about the results of a very recent study of the natural history of Peyronie's Disease. I'm thinking the study suggests that there may be two types of Peyronie's disease, early onset (Type I?) and late onset (Type II?) with an age cutoff of 50.

Fifty is a special age. Throughout most of human evolution men did not live past fifty. Nothing is really designed to last that long; life much past fifty requires a cozy environment and, often, some medical care. So things that go wrong after fifty are often normal "wear and tear". That's a clue.

My guess is that Peyronie's after 50 is mostly a bit of bad luck. The course of late onset Peyronie's is relatively benign. Progression is limited. Symptoms may resolve. It sounds more like an unlucky tear or injury to a sub-optimal tunica albuginea than a true disease. It's a vulnerable structure, sometimes it's less well made, it can tear.

Early onset Peyronie's, developing before age 50, is another story. The disease seems to progress, and may do so without evidence of repeated trauma. This seems more like a pathologic process, a genetic disorder of fibrocyte perhaps.

They may be the same condition of course, or related conditions, but I suspect we'll learn more about Peyronie's if we study early onset and late onset disease separately. If we study them together, we may miss important signals in the noise.

Thursday, July 5, 2007

The shared items page - an article from 1965

In a prior post I described how to create feeds to track publication activity in the National Library of Medicine. Since I'm thinking Peyronie's is probably a systemic disorder of fibrocyte function one of my searches tracks articles that focus on both Dupuytren's contractures and Peyronie's disorder. You can see examples of some of those articles on my shared items page.

This is all about catching the latest news, so I was bemused when one of the articles I found was from 1965 ....

It's in German, so not that easy to follow up, but PubMed lets one track related articles, which included this one from 2004:
Qian A et al. Comparison of gene expression...[PMID: 15302515]

... CONCLUSIONS: These data demonstrate that the pattern of alterations in the expression of certain gene families in PD and DD is similar, suggesting that they share a common pathophysiology and may be amenable to the same therapeutic regimens.
Really, not a lot of progress in 40 years, but maybe things will start picking up ...

How to track research developments using syndication and an RSS reader

One of the ways I track research developments is by using an advanced feature of the National Library of Medicine's PubMed database and Google Reader.*

For example, here is a PubMed RSS feed for "fibrocyte disorder" [1]. If you right click on the link to the left, copy and paste it into a feed reader, you'd see a feed.

Here's what I did:
  1. Go to PubMed. (National Library of Medicine, once upon a time a similar product was called 'Grateful Med'. Those were the days.)
  2. Enter your search string (ex. "fibrocyte disorder" and hit enter.
  3. Now, look carefully atop the results for a drop down "button" called "Send To".
  4. Click on "Send To" and choose "RSS Feed".
  5. Now look for the XML icon and copy the link. Paste into Google Reader.
Here's another one, for example, for Peyronie's Disease. It's easy to create as many as you'd like, and the searches can be much more sophisticated than the simple examples above.

One feature of Google Reader is that you can select interesting articles and share those in turn. The page that one uses to share those can be viewed by a web browser, but it also has a feed. Here's the page, which I'll add to over time:
Incidentally, my standing search on Google News also provides RSS syndication, so I'm including that in my Google Groups Peyronie's collection and items I note of interest will be on the shared articles page too. (Actually, at the moment that service appears to be broken ...)
* A discussion of syndication clients is more than I want to get into. Bloglines and Google Reader are two web based clients, Firefox, IE 7 and Safari have reasonably good built-in readers, and their are several good dedicated readers for OS X and one good reader for XP (Onfolio).

[1] One of the ideas I'm exploring is that Peyronie's Disease is really a systemic fibrocyte disorder that manifests as penile deformation because of the unique vascular structure of the tunica albuginea. If so it should have a relationship to other disorders of fibrocyte function...

Wednesday, July 4, 2007

The course of Peyronie's disease

This is just out: The natural history of Peyronie's disease. [Arch Esp Urol. 2007] - PubMed Result. I'll post later on how I get alerts about this kind of thing, but here are the key results from the study of 110 patients over at least five years (based only on the abstract):
1. Patients over 50 tend to stabilize or get better.
2. Patients under 50 tend to get worse. Almost 70% progressed to surgery.
Studies of the natural history of a disorder are hard to fund and hard to do. We need more of them. I don't know how good this one really is, the trick is how representative the initial sample is and how many are lost to follow-up. In general the patients who do worse tend to follow-up, so results of these studies tend to the "grim" side.

Grim is the word for the under-50 group, I really didn't think 70% would end up with surgery. Given that a significant number may have decided to give up on intercourse, it really contradicts the general impression most urologists have about the course of the disorder.

Conversely older patients can do well, though again I wonder how many just decide to give up.

Needless to say, no medical therapy seems to make any difference. Bad numbers, no doubt.

Why research Peyronies? To understand asthma, heart disease, chronic cystitis ...

If Peyronie's is best understood as a hyperactive fibrosis disorder, then it makes sense to look at other fibrotic disorders for clues to Peyronie's. This 2007 article provides a nice overview of current thinkings on disorders of the fibrotic response (emphases mine, I've always been fond of moncytes ..):
The role of the fibrocyte, a bone marrow-derived m...[Lab Invest. 2007] - PubMed Result

... Human fibrocytes are mesenchymal progenitors that exhibit ... characteristics of hematopoietic stem cells, monocytes and fibroblasts. They likely represent the obligate intermediate stage of differentiation into mature mesenchymal cells of a bone marrow-derived precursor of the monocyte lineage ...

... human fibrocytes produce large quantities of extracellular matrix components and further differentiate into cells identical to the contractile myofibroblasts that emerge at the tissue sites during repair processes and in some fibrotic lesions. ...

...a causal link between fibrocyte accumulation and ongoing tissue fibrogenesis or vascular remodeling in response to tissue damage or hypoxia. Fibrocytes synthesizing new collagen or acquiring myofibroblast markers have been detected in human hypertrophic scars, in the skin of patients affected by nephrogenic systemic fibrosis, in human atherosclerotic lesions, and in pulmonary diseases characterized by repeated cycles of inflammation and repair, like asthma. The presence of fibrocyte-like cells has been reported in human chronic pancreatitis and chronic cystitis. Similar cells also populate the stroma surrounding human benign tumors...

Well, there you go. Perhaps understanding Peyronie's may provide valuable clues for understanding asthma, atherosclerosis (heart disease) and chronic pancreatitis. After all, the lesions of Peyronie's are much easier to biopsy than those of cardiac vessels or pulmonary alveoli. If that's not good for funding, I don't know what is.

I looked earlier for an association between keloid (hypertrophic) scars and Peyronie's, but I couldn't find any. That would be a good question for the Peyronie's Society forum though. For the record, I have both Peyronie's and a nasty keloid scar.

Chronic cystitis is the bane of urologists. One wonders if it could be the female equivalent to Peyronie's. Now I admit that's a bit nutty, but it wouldn't hurt to ask women with chronic cystitis if they have relatives with Dupuytren's contractures (they probably wouldn't know of male relatives with Peyronie's).

Update 7/4/07: After my wild speculation on Dupuytren's and chronic insterstitial cystitis I tried a Google search on the combo and got this tantalizing fragment from last year:
Dupuytren's contracture is associated with sprouting of substance ...
... 10 We propose that Dupuytren's contracture is an inflammatory disease dominated by mast cells, bearing similarities to interstitial cystitis. ...
I swear I didn't know that was out there. Alas, I can't get at the full text of the article, I'll have to try it from my U account another time. It's the only one and it sounds like an aside deep in the text, but maybe my speculation wasn't quite as whacky as I thought it was ...

Peyronie's Disease Society public forum

Peyronie's is a relatively common, though generally concealed, disorder. It may affect as many as 1/100 men, though I suspect the "significant impact" number is closer to 1/300 or so.

For such a relatively common and rather significant (to us) disorder, there's not much on the net -- lots of brief introductions, very little discussion, quite a few scams.

There's one notable exception: the Peyronie's Disease Society - Forum, which is the communication center for the Peyronie's Disease Society. The PDS is so pure it doesn't even seem to have advertising:
... We are non-profit. We have no commercial interests, and are funded solely from the personal finances of our management team. Our membership base actively contributes to information, education, and support, through our Peyronies Disease Forum...
I've browsed the forums, and, given my background, it's not surprising that I'm familiar with most of the science and discussion topics. There's a lot of enthusiasm for topics I'm not interested in (various vitamins, DHEA, etc), but there's also discussion of surgical interventions and results. That kind of data is very hard to find.

I'll be browsing the forums on a semi-regular basis, looking for topics that suggest some literature research.

Clinton has Peyronie's Disease?!

You know, and I say this more seriously than you might imagine, this may explain quite a bit.

This is from the BBC article on PD:
BBC - Health - Ask the doctor - Peyronie's disease:

...Although Peyronie's disease is quite common - it's thought to affect about one in 100 men - few have heard of it. At least they hadn't until a couple of years ago when, in the US, Paula Jones filed a sexual misconduct lawsuit against President Clinton. She swore intimate knowledge of the President by describing a distinguishing penile condition whereby there's a distinctly angled bend visible when the penis is erect...
Maybe I could get Bill to join this blog. I completely shut out all the Paula Jones news, apparently I ought to read the tabloids more closely.

Other than that fragment of some interest, there's not much else in the BBC essay, indeed it's quite dated.

Pathologic fibrosis: implications for treatment and research

We suspect that Peyronie's is a genetic disorder, in some cases inherited, that is characterized by hyperactive fibrosis. Although Peyronie's is a disorder of the tunica albuginea of the male penis, it's likely that the hyperactive fibrosis manifests throughout the body (pathologic scarring?).

So what are the clinical implications of this knowledge?
  • urologists should be wary of urologic procedures in men who have relatives with Dupuytren's contracture (or Peyronie's, but they won't know of the latter).
  • research in other disorders characterized by pathologic hyper-fibrosis may have implications for understanding Peyronie's -- and vice-versa. (I'll be looking to see if there are any such disorders with significant funding. Hmmm. Maybe fibrosis in the intima of cardiac vessels?)
  • the best treatment for Peyronie's will probably be a locally applied medication that reduces fibrosis and is administered with very early symptoms in persons with a known predisposition (eg. family history) of the disorder

Peyronie's and chromosomal abnormalities

In my prior post I reviewed the OMIM entry on Peyronie's. That entry cited a 1987 and a 1991 (yeah, research is slow in this domain) article on chromosomal anomalies in the abnormal plaque tissue of the tunica albuginea found in Peyronie's disease.

These articles make the plaques seem more like a tumor than a conventional scar. Pubmed lets one query for "related articles" on a given topic, here's what that query looks like:
One of the articles that turned up was interesting, emphases mine:
Mulhall JP et al. Chromosomal instability is de...[PMID: 14961053]

... Peyronie's disease is a fibrotic disorder, a condition characterized by cellular proliferation and excess extracellular matrix production. Previous work in related conditions has demonstrated chromosomal instability. This investigation was undertaken to analyze fibroblasts derived from Peyronie's disease tunical tissue for abnormalities of chromosome number and progression of cytogenetic aberrations during cell culture...

... Peyronie's disease plaque-derived fibroblasts demonstrated frequent aneusomies in chromosomes 7, 8, 17, 18 and X and recurrent deletions of chromosome Y. Peyronie's disease nonplaque tunica-derived fibroblasts demonstrated infrequent chromosomal changes early in culture; however, with repeated passaging the majority of cell cultures demonstrated aneusomies [ed: extra copies] in at least one chromosome. These data indicate that Peyronie's disease plaque-derived fibroblasts have consistent aneusomies even at early passage and that nonplaque tunica-derived cells from men with Peyronie's disease also demonstrate chromosomal instability. This suggests that the tunica albuginea of men with Peyronie's disease may be predisposed to undergoing unregulated fibrosis. These findings confirm the transformed nature of the Peyronie's disease tunical fibroblasts studied in this analysis. While the etiology of these findings is not clear, it is likely that these pathobiological characteristics contribute to the pathophysiology of this disease process.
In other words men who develop Peyronie's Disease have something wrong with all the cells of their "tunica albuginea", not only those involved in Peyronie's. Of course this implies there's something wrong with at least those cells everywhere in the body.

In particular the cells are prone to a crazed kind of fibrosis (tough fiber generation) instead of a reasoned, measured, sort of fibrotic reaction.

It would be interesting to know what other conditions this presumably genetic defect may predispose to -- besides Dupuytren's contracture.

From a science point of view, this study tells us something fairly interesting. There's very little active research in Peyronie's, but it's studied using tools that are developed for other, actively studied, domains. A competent researcher can simply repeat a study from 10 years ago, and by virtue of better tools new knowledge will emerge.

OMIM - The Peyronie Discussion

OMIM, the "online mendelian inheritance in man" NIH database, published out of Johns Hopkins, is a formidable reference source. The discussion of "Peyronie Disease", however, is a bit eccentric. For example: "An anonymous nongeneticist suggested to me in 1980 that Peyronie disease is 'sex-linked with reduced penetrance.'" Cough. That doesn't show up in most of the OMIM posts, I get a feeling this one is under-edited.

Even so, I've excerpted and bolded some sections.

... Bias et al. (1982) concluded that this phenotype is a male-limited, autosomal dominant trait. They traced Peyronie disease through several families. Dupuytren contracture was often present in both males and females. In 1 kindred, males in 3 successive generations had Peyronie disease and Dupuytren contractures, and the latter was present in a fourth generation. Close linkage with HLA (see 142800) was excluded. Chromosomal abnormalities were described by Somers et al. (1987) and by Guerneri et al. (1991).

In Rome, Carrieri et al. (1998) performed a case-control study of 134 men with Peyronie disease and 134 male controls. Men who had undergone invasive procedures on the penis (e.g., urethral catheterization, cystoscopy, and transurethral prostatectomy) had a 16-fold increased risk of Peyronie disease, while a nearly 3-fold increase was observed among men who had genital and/or perineal trauma. ...

... Dupuytren contracture was found in 21% of cases and none of the controls, and 4% of the cases and none of the controls reported familial history for Peyronie disease.

Note that the key research on the genetics of Peyronie's was done twenty-five years ago, and yet it's omitted from most discussions of the disorder (I'll be adding it to Wikipedia.) I was very surprised by the 16-fold increase with urethral catheterization.

If I were a urologist, I would routinely ask prior to any urologic procedure whether the patient had any relatives with Dupuytren's contracture. If they did, I'd reconsider the need for the procedure. A 16-fold increase is enormous.

It's most likely that Peyronie's Disease is a pathologic reaction to common micro-trauma of the penile vasculature. Men who don't carry* the gene may develop small scars or non-significant plaques, men who carry the gene* develop plaques and pathologic scarring.

* Genetics is far more complex than it once was. Now when we say "carry" we mean something like "a complex of interacting genetic material" with one or more interacting mutations.

Peyronie's disease - the Wikipedia article

The primary purpose of the blog is provide material I'll use to make the Peyronie's disease - Wikipedia article as robust as possible.

As of 7/04 it's a very brief article, but it's pretty high quality. I'll be gradually expanding and adding to it.

What is it like to have this disease?

How bad is it to have Peyronie's?

Well, it won't kill you, it's not contagious (though a predispositon to the disease is inherited) and it won't prevent most kinds of employment. On the other hand, if you get severe Peyronie's before age forty you have a right to feel that life has seriously dumped on you. If you get it after age 70 (unlikely) you probably can't complain quite as much.

I think for most of us the impact is similar to losing an eye (one, not two), a hand, or developing a treatable malignancy. It's a big personal impact and it takes a significant amount of time to work through.

Why the URL?

The url for this blog is "thebentnail.blogspot.com". This old colloquial name for "penile induration" (Peyronie's Disease) wasn't my first choice, but "peyronies.blogspot.com" and "peyroniesdisease.blogspot.com" were taken by "blogspot squatters".

So we go with the funny one.

About this blog

I have Peyronie's Disease, also known as "penile induration" and sometimes informally called "bent nail syndrome". I've had it for about thirteen years, but an exacerbation a year ago took it from moderate to severe and effectively "disabling".

This is not a common disease, but it's not as rare as you might think. It's not something men tend to talk about. I suspect the disease runs in my family since several male relatives have "Dupuytren's contracture", a related disorder -- but nobody talks about their broken organs. I think that's understandable. There's a reason this blog is published under a pseudonym.

There's not much research into Peyronie's disease, and our knowledge of the disorder has progressed very little since the 1980s. There are no effective medical therapies, few clinical trials, no drug research, and the surgical treatments are nothing to brag about. There is lots of misinformation and a bit of exploitation.

Although I'm a physician, I won't be dedicating my life to researching the disorder. I've got other commitments I have to follow. I would like, however, to spin something positive out of my affliction. I intent to contribute to the wikipedia page on Peyronie's, and to use this blog to help build that material. I will also market it a bit for those who might be interested in my own personal perspective.

This blog is my personal perspective. I'm sympathetic to the desperation that drives people to "alternative therapies" (Vitamin E, alas, is now in that category), but I'm a science guy. So, no alternative therapies, none of the various scams, nada. No ads either.