Interview with Dr Keith Denkler

Today I have an interview with a specialist, this is the first time in about a year that I am doing one of these posts but hopefully there will be several more of them in the coming weeks as I try to branch out and discuss the treatment options with specialists from around the world. I am quite keen to talk to any specialists in the USA, particularly those doing radiotherapy, this is because I am often asked about them by people e-mailing me and it would be nice to give a good answer. So if you have been treated in the US then please get in touch and if you can let me know who you were treated by and if you have contact details (especially e-mail) please provide them. Thanks. 

Right onto today. I was browsing the web last week looking for a Dr or two to pester about these conditions, I thought it would be great to chat to someone who has done the surgery and I came across the following website with loads of information: 

http://www.plasticsurgerysf.com/dupuytrens/

There is a lot of good information on there so I thought that this person would likely be well informed and was worth contacting, I sent him an e-mail and although he was happy to help he did admit to not having done surgery on many Ledderhose patients but has seen a lot of patients, here are the answers I got. Some are not as detailed as I would like but the professionals are of course very busy so any response for a blog is a great result.

 Dr Keith Denkler  

Profile (from his website): (Information posted with permission from website listed above)

Dr. Denkler has been practising medicine since 1989 in Marin County, California. His practice includes both plastic (aesthetic-cosmetic) and reconstruction surgery. Dr. Denkler has achieved board certification in both plastic and hand surgery and teaches as a Clinical Professor of Surgery at UCSF Medical School. Dr. Denkler is one of the few doctors offering treatment for Dupuytren's contracture using the French needle technique called NA (needle aponeurotomy), a type of subcutaneous fasciotomy Dupuytren's in addition to XIAFLEX™. Dr Denkler is still based in California.

This page may be of interest for Dupuytren's patients: http://www.plasticsurgerysf.com/scrapbook/

Now on to the interview: 

1) How long having you been treating Dupuytren's and Ledderhose disease?  

I have been treating these conditions for almost 25 years.

2) Roughly how many Dupuytren's patients have you treated and how many Ledderhose patients have you treated?

I have treated thousands of patients with Dupuytren contracture and have seen hundreds with Ledderhose.

3) What treatments have you used for these conditions? Would you recommend the treatment and roughly how successful is the treatment for each condition?

 

My treatments are predominately needle and or Xiaflex/Xiapex. I only occasionally do surgery.  Ten years ago I did only surgery, using the wide awake technique which I developed.

https://en.wikipedia.org/wiki/Dupuytren%27s_contracture
For Ledderhose, I occasionally have excised, wide-awake, but scar tissue tends to replace the Ledderhose.  I have done this in about half-dozen patients. 

I have done a few dozen needle aponerutomies for Ledderhose, which can give some improvement in severe cases.
 

I also inject Kenalog(cortisone) which can soften nodules.
 

Xiaflex/Xiapex may have a role, but the it is very tender and sore for some weeks and my experience is limited to a few patients with small doses.  The extra enzyme from the hand can be legally used on the feet.  Otherwise the enzyme is not approved in the USA for Ledderhose.

Mostly I recommend starting with Kenalog injections, then needle, and then perhaps wide awake surgery or enzyme.

There is no optimal treatment.  Freezing (which I don't do) may be beneficial.

4) What would your recommendations be to Dupuytren's and Ledderhose patients and do you have any advice you would like to give?

These are chronic conditions and are managed, not cured.

Keep the treatments simple with needle, or enzyme, or both.  Save surgery (has highest complication rate) for severe cases not amenable to the other treatments.

Overall there are some very interesting points that he makes, in questions 4 he mentioned keeping the treatments simple but he does not mention radiotherapy, in fact it is not mentioned anywhere in his report. It is mentioned, although briefly, on his website that I linked to above. 

It is interesting that the technique of choice in the last 10 years, for Ledderhose at least, has shifted from " Ten years ago I did only surgery," to now "Save surgery for severe cases not amenable to the other treatments." whether this is just because he now does the other treatments or because the optimal treatment path has changed I don't know, of course Xiapex was not available.

 

Late complications with Collagenase injections?

Today I got an e-mail telling me that there was a new paper out relating to Dupuytren's (thank you Google Alerts), so I went and had a look and it is another paper that is looking at collagenases such as Xiapex/Xiaflex. For those who don't know these are enzymes that break down the main complex that forms the cords in Dupuytren's and I have heard that it does have some positive influence on nodules as well. 

For background information see some of my previous posts which include: 

• Interview with a Hand specialist in the UK who administers Xiaflex 
• Interview with a patient who has had Xiaflex 
• Some science on it working in cells

 Still in this paper they are looking at patients after a time that is greater than that used in the phase III (the final phase) clinical trials:

Late Complications of Clinical Clostridium Histolyticum Collagenase Use in Dupuytren's Disease - It is an open access article so anyone can go and have a look and if you don't understand anything then please ask me questions and I can probably agree that I didn't understand either - Warning there are some graphic pictures of procedures being performed on a hand so don't look if you can't stand that sort of thing. 

What do they find: 

2 of 12 patients had problems. 

Well the typical follow up period in the trials was 3 months and here they go up to a year in what is unfortunately a small sample group of only 12 patients and they find that: (Just because I like at least one picture per blog post): 

Although the majority of the patients are fine 2 do have side effects, in the pie chart this may look like a small amount but imagine this applied to 1200 people rather than 12 and suddenly that is 200 people with problems. 

These two patients had significant disability in the injected hand and also suffered from pain and in both case operative intervention was taken a year after the treatment with the collagenase. They found that there was deep tissue scarring that was presumably caused by the injection and that this could be the cause of finger stiffness and pain. They then waffle on about science stuff and come to the conclusion that long term problems is something that those administering this drug should consider both before and after giving the treatment. 

If you are interested in learning more about this then please e-mail me, post a comment or hop over to the forum and share your story at the same time.  

Xiaflex works on condition other than Dupuytren's

I mentioned ages ago that I had signed up for a Google Alert for Dupuytren's and this has proved to be very helpful over the last few months and this weekend my phone has been buzzing so much with the same alert over and over again it is crazy. 

I mentioned the news that Xiaflex works for Peyronie's disease was announced in Nature this week in my post on the new Pfizer "It is in your hands" post and well that has been a big hit this week and here is some of the titles that I have been getting: 

• Penis too curvy from Peyronie's disease? A new drug might help 

• Why Auxilium Pharmaceuticals Shares Popped

• Treatment for Penis Curvature Sees Results

• Auxilium Pharmaceuticals, Inc. Announces Positive Top-line Results from Both Phase III Trials of XIAFLEX® for the Potential Treatment of Peyronie's Disease Source: PR Newswire (http://s.tt/1di6m)

Well that is a taster of them anyway. Interesting to also hear that they are looking at testing if for frozen shoulder as well. 

News article on Dupuytren's

Today I thought I would have a look out there and see if there was any news around about Ledderhose disease and of course a quick search in Google News revealed that there was nothing so I tried a search for Dupuytren's instead knowing that this is more common and seems to hit the news more often. Sure enough there were some hits (though still not that many) but looking through them one caught my eye so I thought I would do a post on it.

The article in question is called "The solution is close at hand" and was written by Adam Greenberg of the Clifton Journal and can be found here.

This report looks at a patient being treated with Xiaflex and how it is used to treat patients with Dupytren's and how this is the 3rd success story from this particular Doctor. The report states that this patient is on their third treatment and that it seems to be working very well. In fact if you read this you will see that the doctor even goes so far as to say that patients may start to see results within "days" and that Surgery takes longer to work than this and has a poor long term outcome.

The patient, an 80 year old man said that he is the only person in his family that has the condition and had given up on something being done in his lifetime (well words like that anyway). He found that just days after the first treatment he had increased movement in his fingers.

Overall this is a very positive article and it is going to be interesting to see if this drug or indeed a similar one can take off and be cheap enough for blanket approval on the NHS here in the UK. After all you would think that treatment with something like this is much cheaper than having someone in for surgery and if the results do turn out to be as good then surely it has to be considered. It is good to see Dupuytren's in the news although it would be nice for a change to see if we can get Ledderhose in the spotlight, anybody have any ideas?

Xiaflex in cells - Trying to help you understand, maybe

So today I am going to try and review this paper In Vitro Study of Novel Collagenase (XIAFLEX®) on Dupuytren's Disease Fibroblasts Displays Unique Drug Related Properties. This paper is open access so you might like to take a look for yourself or have it open at the same time as you read this and it might help. I don't understand all of it so good luck!

I say try because there is a lot of scientific content in this paper, a lot of stuff that I have not done in the lab before and this makes it harder for me to work out exactly what it means, I will however try my best to understand it and where possible try and explain it in as simple terms as possible.

To start with for those who don't know Xiaflex is a treatment for Dupuytren's disease (DD) and potentially Ledderhose disease (LD), it is a collagenase and the main component of the lumps in DD and LD is collagen and so it breaks them down.

Right onto the paper, where possible I shall try and bullet point it and I am going to place a summary at the end where I will put what I consider to be the key points.

Introduction:

• DD is a common and benign disorder. 
• The cause(s) of DD and LD are unknown however DD has been linked to genetics, smoking, diabetes, alcohol, anti-epilepsy medication, occupation and local trauma (so all the usual stuff). 
• The group of people at the most risk are Caucasian men of North European descent that are 40 or over with highest incidence in USA, Scandinavia, Britain and Australia. 
• The disease shows cell proliferation, high levels of collagen and extra-cellular matrix remodelling. 

They also make a key point which is what frustrates many of us with the disease and this is that:

"Treatment of DD is not curative" and this means that rather than trying to rid the body of the disease they are just trying to remove the symptoms.

One current treatment that is showing promise is Xiaflex which is a collagenase that digest the triple helical structure of collagen and therefore removal the lumps and whilst this is significantly less invasive than surgery it does have a much higher level of recurrence.

Aim: Their aim is to investigate the functional effects of Xiaflex in comparison to Collagenase A when used on cells cultured from DD nodules, cord, fat and skin. They look into various different aspects of the cells including looking at the cell growth and at gene expression.

So I am going to try and go through this and explain the key points one figure at a time to make it easier to follow.

Figure 1: Here they just show the process through which they have derived the cells and then the experiments that they are planning to do on them.

Figure 2 (and Figure 3): Here they are measuring the ability of the cells from the DD nodules and cords to grow in the presence of  Xiaflex / Collagenase A and whether they are able to recover from this treatment in 24 hours by removing the drug and continuing to monitor the cells. In Figure 3: They also look at fat and skin cells from DD patients in a similar way.

• They find that without treatment there is no significant different between the nodules and cords compared to the skin and fat although the DD nodules and cords do show a faster growth rate. This makes sense as it is a proliferative disease.
• Treatment with  Xiaflex / Collagenase A decreases all of the things that they are measuring in ALL cell types in a dose dependent manner. 
• 24 hours after removal of the drug the cells recover, this happens even at the highest dose and may help to explain why DD comes back so frequently when treated with  Xiaflex. 

Figure 4: I can't really follow this figure very well so rather than get it wrong and make mistakes I am going to leave this figure out but their key point from this seems to be that Xiaflex / Collagenase A induce membrane leakage and reduce cellular viability and metabolic activity in DD cells.

Figure 5: Here they are looking at the toxicity of the 2 different drugs and want to see which is more toxic to cells and if there is any specificity towards DD nodules and cords. 

• Xiaflex / Collagenase A both cause cells to die. 
• Collagenase A causes both necrosis (premature cell death) and apoptosis (programmed cell death) 
• Xiaflex only causes necrosis.

As far as I can tell from reading this (and correct me if I am wrong) they do not comment on whether this is a big deal or anything? But I think they say in the discussion that it may mean that there are likely to be viable DD cells and therefore there is an increased chance of disease recurrence. 

Figure 6: Here they are looking in the different types of cells at the levels of mRNA for key components in the production of collagen to see if this is altered by the presence of Xiaflex / Collagenase A. For those who don't know about the central dogma of life I have tried to outline it in the diagram below. But the key thing you need to know to understand these results are that mRNA is produced from DNA and that the levels of mRNA vary so that it can be used as an indicator of protein levels in the cell as protein is produced from mRNA. (Below image is VERY simplified)

The central dogma: DNA is where the information is stored and this is processed into RNA and then proteins. 

• They are looking in DD disease and see that  Xiaflex treatment causes a decrease in levels of collagen I and collagen III as well as fibronectin (forms part of ECM and interacts with collagen), alpha SMA and TGF-B1. If you remember from my previous post a decrease in TGFB1 would be useful. Explained in the image below. 

Central blue boxes show state in DD cells, right hand side is reported influence of Xiapex in DD cells

• They also say that levels of collagen are at their highest in the DD nodule which is exactly what you would expect. 

Figures 7 & 8: In figures 7 and 8 they are looking at the protein levels of Collagen I and III in the different cells types to see a) is there any difference in their profiles between the different sources (skin, fat, nodule and cord) and b) does Xiaflex / Collagenase A treatment cause any changes to these levels. 

• They show that the levels of Collagen I and III in the nodules are very high with Collagen III in particular very, very high (basically two times more than seen in anywhere else). 
• When looking at the effects of Xiaflex and Collagenase A they see that: 
• Collagenase A has an influence on Collagen I by causing a decrease on all samples at the highest dose only. 
•  Collagenase A only decreases Collagen III at the highest 2 doses in the nodules, cords and fat.
• Xiaflex causes a large decrease on all samples at all doses for both Collagen I & III with the largest decrease observed in the Nodules and cords.  

Figure 9: Here they are trying to show that the decreased levels of Collagen and other ECM factors was not just at the mRNA level but that they were also decreased at the protein level when DD tissue was treated with Xiaflex. 

• Xiaflex does down regulate the protein levels of fibronectin, Collagen and CTGF (and more) at  the protein level. 

Figure 10: I am just going to say that they see that Xiaflex and Collagenase causes a decrease in cell cycle markers. This makes sense as when the drug is added you see a slowing on cell growth and this means that the cell cycle is slower and therefore you should have a decrease in cell cycle related proteins (though in this case they are look at mRNA).

Right so that is all that I am going to cover for this paper, as I said it is a long post and it is very science based so here is the summary for all those who just want the key points or who are just too lazy to read it all (which is fair enough). 

Summary: 

• DD nodules and cords do show a faster growth rate.
• Xiaflex and collagenase A both decrease the growth rate in DD cells. 
• Xiaflex treatment causes a decrease in levels of collagen I and collagen III as well as fibronectin  and TGF-B1 (see the diagram as to why this might be good). 
• Levels of Collagen I and III in the DD nodules.

Reference:
Syed F, Thomas AN, Singh S, Kolluru V, Emeigh Hart SG, et al. (2012) In Vitro Study of Novel Collagenase (XIAFLEX®) on Dupuytren's Disease Fibroblasts Displays Unique Drug Related Properties. PLoS ONE 7(2): e31430. doi:10.1371/journal.pone.0031430