Dupuytren Roundtable Discussions

Here are links to two recently published roundtable discussions by experts in the field of Dupuytren's. Although these were discussions by surgeons for surgeons, they are really just conversations and quite readable. They highlight the current challenges both surgeons and their patients face with Dupuytren's disease and provide insight into future efforts to develop a biological cure.

American Association of Hand Surgeons (go to page 6): http://www.dupuytrenfoundation.org/DupPDFs/2010_AAHS.pdf

American Academy of Orthopaedic Surgeons: http://www.dupuytrenfoundation.org/DupPDFs/2011_AAOS.pdf

Coming up: What is known about Dupuytren's and Chondroitin/Glucosamine?

Stony Brook Dupuytren Symposium

I had the opportunity to attend the Stony Brook Dupuytren Symposium April 17. This was a real treat, featuring a faculty of well known authorities on Dupuytren's. The volcanic ash European flight difficulties prevented attendance of only one speaker. The symposium covered a range of topics and in addition provided an in depth tour of the use of collagenase injection for Dupuytren's from the initial concept, through proof of concept in laboratory tests and then clinical trials, to clinical application, indications and issues. This is a monumental achievement for Drs. Hurst and Badalamente, and a testimony to their insight and persistence. Plans were also discussed to jointly present the materials from the Stony Brook and the upcoming Miami Dupuytren Symposium (http://www.DupuytrenSymposium.com) together as one book, to be published by the American Society for Surgery of the Hand (http://www.assh.org). What a promising year for Dupuytren's!

Personal experiences with Xiaflex and Needle Aponeurotomy

Xiaflex is now available, and is generating reports by both traditional writers and self published social media authors. There are now two minimally invasive treatments for contractures due to Dupuytren's disease - Xiaflex injection and needle aponeurotomy - with relative advantages and disadvantages of each. The following video was made by a Dupuytren's patient, documenting experience with needle aponeurotomy: http://www.youtube.com/watch?v=lGD9RjmFBzo. Another person's documentary experience with Xiaflex, also with videos, is posted here: http://bit.ly/9RhqQA. Their experiences were different, but both are satisfied with their results. Every hand is different and no one treatment works for everyone, but it's great that there are new options to choose from to buy time while researchers work for a cure. The Dupuytren Foundation is actively recruiting volunteers and fund raising options to develop better treatments - and eventually a cure. Support the effort. Make a difference. http://www.DupuytrenFoundation.org

Metalloproteinases and Dupuytren's

A better understanding of the biology of metalloproteinases may lead to new treatment options for Dupuytren's. Metalloproteinases (MMPS) are a group of enzymes in our bodies which break down certain proteins, including collagen. MMPS are blocked by tissue inhibitors of metalloproteinases (TIMPS). MMPS and TIMPS balance each other: imbalances have been implicated in conditions of excess collagen, as seen in Dupuytren's, or inadequate collagen leading to rotator cuff tears. The article "Metalloproteinases and their inhibitors—diagnostic and therapeutic opportunities in orthopedics" (full text: http://www.dupuytrenfoundation.org/DupPDFs/2009_Pasternak.pdf) is a clearly written and thorough review of the topic and its implications for Dupuytren's and other conditions. MMPs are involved in the biology of inflammation and wound healing, which overlaps the cell biology of Dupuytren's. The authors note "In view of the strong hereditary component and a predilection for men in Dupuytren’s disease, it is interesting to note that TIMP-1 is located on the X-chromosome." It may not be that a man's Y chromosome puts him at special risk, but that a woman's X chromosome offers her special protection. In addition to involvement with Dupuytren's, MMPs and TIMPs appear to play key roles in unrelated disorders including arthritis, degenerative disk disease, tendinitis, fracture healing and other conditions. Inroads made in understanding their role in Dupuytren's are likely to benefit people suffering from other conditions - an added incentive to work for a cure.

Stony Brook Dupuytren Symposium

What a year for Dupuytren's! Xiaflex is FDA approved, the 2010 International Symposium on Dupuytren's Disease http://www.DupuytrenSymposium.com is coming up May 22,23 in Miami, and now Stony Brook University Medical Center Department Of Orthopaedics has announced its Dupuytren’s Disease Symposium Saturday, April 17th, 2010 in Stony Brook, New York. The program flier is http://sbumc.informatics.sunysb.edu/sbumcfiles/Dupuytrens%20brochure.pdf. The program lists an international faculty and reviews Dupuytren's biology in addition to a spectrum of management options to straighten fingers bent by Dupuytren's. The Stony Brook Symposium will be a perfect complement to the Miami Symposium's goals of presenting new research and establishing a coalition to work toward a cure for Dupuytren's disease and related conditions.

Xiaflex Pricing

Auxilium has moved closer to product availability of Xiaflex collagenase injection for the treatment of Dupuytren's contracture by announcing the wholesale drug price: $3250.00 for a single treatment dose. For those who think that this seems high, consider this in perspective. There are many categories of pharmaceutical products. Most commonly available pharmaceuticals are classified as "small molecule" drugs: organic compounds "small" enough to be able to be absorbed directly into cells. Some small molecule drugs, such as morphine, penicillin, aspirin and cortisone have been used for years; others are new, like the cancer drug Gleevec. In contrast, "biologics" are complex large molecule organic compounds. Biologics are much more difficult (expensive) to purify than small molecule drugs. They are often produced using costly recombinant DNA technology. Biologics include Enbrel for rheumatoid arthritis, Botox for spasticity, and now Xiaflex for Dupuytren's contracture. Each of these biologics reduces the need for surgery for a specific condition. They are expensive, but cheaper than surgery. Who is going to pay for Xiaflex? The same sources that pay for surgery: private insurance, Medicare, or, if neither is available, the patient. The paperwork will be different, but the process will be quite similar. Auxilium has a patient information site http://dealingwithdd.com and physicians can call 1-877-663-0412 to get more information. Xiaflex cost should be compared not just to open surgery, which is widely available but more expensive, but also to needle aponeurotomy, which is less expensive than Xiaflex but available at fewer centers. Confusing? Somewhat, but it's great to have several options for treatment while we continue work to develop a true cure.

Needle Aponeurotomy and Xiaflex compared

Xiaflex (Collagenase) has finally been approved by the FDA for the treatment of Dupuytren's contracture. When work began on the development of collagenase to treat Dupuytren's contracture, the bar was pretty low: anything better than fasciectomy in terms of either safety or efficacy would be a great advance. No other treatment options were available in the United States. However, during the time that research was being performed on collagenase, needle aponeurotomy was introduced into the US and has gained some popularity. This changes the equation for collagenase - it's no longer the only alternative to fasciectomy. How will this play out? Read this comparison of needle aponeurotomy and Xiaflex (full text: http://handcenter.org/newfile20.htm) and decide for yourself.

Genes, enzymes and Dupuytren's: the alphabet name game.

A proteinase is an enzyme which breaks down proteins. Metalloproteinases (MPs) are proteinases with a molecular structure and function involves a metal atom, usually zinc. Matrix Metalloproteinases (MMPs) are MPs which act outside of cells, in the tissue matrix. Human collagenases are MMPs which break down different types of collagen. Membrane-type MMPs (MT-MMPs) are MMPs which are attached to cell membranes and protrude into the extracellular matrix. ADAMTS (A Disintegrin And Metalloproteinase with Thrombospondin Motifs) are another subgroup of MMPs. ADAMTs cut off or shed portions of proteins which protrude out of the cell wall, and are classified as sheddases (I am not making this up). TIMPs (Tissue inhibitors of Metalloproteinases) block the action of MMPs. This lecture handout outlines investigation of which genes relating to MMPs and ADAMTs are activated in osteoarthritis and Dupuytren's disease (full text: http://www.dupuytrenfoundation.org/DupPDFs/2007_Clark.pdf). In active Dupuytren's disease, five genes were involved: MMP13, which codes for collagenase 3 (breaks down type II collagen (in cartilage), and to a lesser extent types I and III collagen (in Dupuytren's cords); MMP14 codes for MMP-14, a MT-MMP collagenase which activates collagenase 3 and is activated by poor circulation; ADAMTS5, which codes for aggrecanase, an ADAMTS which breaks down cartilage; ADAMTS14, which is linked to procollagen processing; ADAMTS16, which codes for an enzyme whose function is unknown. More information on this is available here: (full text: http://www.dupuytrenfoundation.org/DupPDFs/2008_Murphy.pdf). Dupuytren's is somehow related to the way that all of these genes interact. Here's a simple question based on all of this: if Dupuytren's is related to not enough collagenase function, and zinc is needed for collagenase to function, and EDTA is an additive put in soda pop because it removes metals such as zinc, could drinking too much of your favorite carbonated beverage raise your risk for Dupuytren's?

LSD as a treatment for Dupuytren's?

There is one published report of Dupuytren's being cured, fingers suddenly straightened, under the influence of the psychedelic drug LSD (full text: http://www.dupuytrenfoundation.org/DupPDFs/1966_Solursh_1417.pdf). Is this true? Probably not. LSD is a serotonin antagonist, and other serotonin antagonist drugs, such as methysergide, have been shown to cause retroperitoneal and cardiac valve fibrosis. Based on this information, LSD might be exactly the wrong drug to take for other fibrotic conditions such as Dupuytren's. The search continues.

FDA approves Collagenase for Dupuytren's

Collagenase (Xiaflex) has been approved by the FDA for treatment of Dupuytren's contracture, after years of intensive laboratory and clinical trials. Collagenase enzymatic  fasciotomy is more similar to needle fasciotomy than to either open fasciotomy or fasciectomy in terms of rapid recovery and low complication rate. Compared to needle release, collagenase enzymatic fasciotomy should eventually be more widely available (because it is easier for surgeons to learn), takes less time to perform, but provokes more inflammation and will be more expensive. Auxilium's press release (full text: http://www.dupuytrenfoundation.org/DupPDFs/2010_Auxilium1.pdf) and physician prescribing information (full text: http://www.dupuytrenfoundation.org/DupPDFs/2010_Auxilium2.pdf) are now available. We live in exciting times for Dupuytren's because for nearly 200 years, there has been essentially one treatment option, surgery, but within the last few years, this has expanded to also include needle release, dynamic fixation and now enzymatic fasciotomy. This has led to greater awareness of Dupuytren's. It is now time to transform this awareness into support for efforts to develop an actual cure.

Dupuytren's Genes

The hunt is on for the genetic basis of Dupuytren's. A interesting analysis of the chromosome patterns found in Dupuytren's tissue found a variety of genetic abnormalities and the unexpected finding that these variations were not found in the skin but were seen in areas of palmar fascia not usually involved with Dupuytren's. (full text: http://www.dupuytrenfoundation.org/DupPDFs/1988_Wurster-Hill_1091.pdf). Twenty years after this report, the hunt is still on with more sophisticated equipment, identification of involved genes closer but still elusive: http://dupuytrenfoundation.blogspot.com/2009/11/gene-expression-in-dupuytrens.html. Still, so many questions: is it determined by one or several genes? If, as widely believed, the trait is a dominant gene, why is Dupuytren's more common in people with blue eyes, the result of a recessive gene? Does the genetic effect only involve the palmar fascia or all fascia? Dupuytren's skips generations and often appears with no family history: is it a common spontaneous mutation, and if so, is it more common in those born to older parents? Some day, these questions will be answered. With persistence, some day, there will be a cure.

Luck and Dupuytren's

Needle aponeurotomy for Dupuytren's is not that new. It's a new twist on the very first operation described for Dupuytren's, percutaneous fasciotomy, which was performed by Cooper years before Dupuytren's famous presentation. Adams wrote extensively about his results with percutaneous fasciotomy for Dupuytren's in the late 1800s. Before Lermusiaux began using a needle for percutaneous fasciotomy and calling it needle aponeurotomy, the last doctor to have much experience with the technique was Vernon Luck, who used his own "Luck Fasciotome", a tiny knife made in his machine shop, to perform percutaneous fasciotomy. Luck reported his concept of the biology of Dupuytren's along with his experience with his technique, and it's an interesting read. (full text: http://www.dupuytrenfoundation.org/DupPDFs/1959_Luck_1074.pdf)

ß Catenin, Transforming Factor ß and Dupuytren's

The physical changes associated with Dupuytren's are similar to the process which heals open wounds through contraction and collagen production. Thanks to sophisticated laboratory research, the molecular controls for this process are beginning to be understood. See http://multimedia.mcb.harvard.edu/anim_innerlife.html for an amazing animation of how molecular cellular controls act like tiny physical machines. In Dupuytren's, two controls are ß Catenin and Transforming Factor ß. ß-catenin is a protein which is part of the physical scaffolding in a cell. Among many functions, ß-catenin forms part of a cellular trailer hitch which locks one cell to the next, called the adherens junctions (AJs). Transforming Factor ß is a protein which is produced by some cells to activate receptors on other cells, part of the autocrine system of cell signaling. It has different effects in different situations. Both ß Catenin and Transforming Factor ß are major players in Dupuytren's type tissue contracture. How do they interact with each other? Somewhat independently, according to this study (full text http://www.dupuytrenfoundation.org/DupPDFs/2009_Poon.pdf). ß Catenin primarily activated cell migration while Transforming Factor ß mainly stimulated cell growth and contraction, which would seem to be the more important process in Dupuytren's. Interesting, but more details are needed to crack the code to find a cure.

A Sampling of Patient Information Brochures on Dupuytren's

What do health care providers think you should know or want to know about Dupuytren's? Here is a sampling of patient information materials from the government http://www.dupuytrenfoundation.org/DupPDFs/2010_NHS-ptinfo.pdf, http://www.dupuytrenfoundation.org/DupPDFs/2010_OBS-ptinfo.pdf, organizations of hand surgeons http://www.dupuytrenfoundation.org/DupPDFs/2010_AAHS-ptinfo.pdf, http://www.dupuytrenfoundation.org/DupPDFs/2010_ASSH-ptinfo.pdf, http://www.dupuytrenfoundation.org/DupPDFs/2010_BSSH-ptinfo.pdf, individual physicians and hospitals http://www.dupuytrenfoundation.org/DupPDFs/2010_eHand-ptinfo.pdf, http://www.dupuytrenfoundation.org/DupPDFs/2010_KWO-ptinfo.pdf, http://www.dupuytrenfoundation.org/DupPDFs/2002_Hurst-ptinfo.pdf, http://www.dupuytrenfoundation.org/DupPDFs/2010_Lancashire-ptinfo.pdf and hand therapists http://www.dupuytrenfoundation.org/DupPDFs/2010_Kramer-ptinfo.pdf. Of course, a wide range of information is also available on the Dupuytren Foundation web site: http://www.dupuytrenfoundation.org/What-is-Dupuytrens