Dupuytren's Practice Blog

 I saw a new blog post by Dr Shaffer posted recently and it is worth considering reading it. The content relates to when is it too early to get RT for Dupuytren's? Now while I know from experience and Dr Shaffers comments the case for Ledderhose is slightly different, however it is good to be knowledgeable that it is not always the right time to have Radiotherapy. 

The Dupuytren's Practice Blog Post

I won't go into the post in detail because that is what the link is for. I have also seen some YouTube videos by Geesis care that I plan on reviewing. There is also a paper on low dose radiation therapy for benign conditions. 

I originally only scanned the article but noticed TGF mentioned which I had covered previously in a post on the pathways linked to the development of Dupuytren's. Be interesting to see whether the proposed mechanism of action of RT / pathways impacted is the reverse of the expected for the cause of Dupuytren's. 

Calorie Restriction to help Dupuytren's and Ledderhose?

A literature review to analyse the link between calorie restriction and pathways associated with Dupuytren's disease

Over recent weeks I have heard several patients talking about calorie restriction and how eating a low calorie diet really seems to help with the pain that they were experiencing with Dupuytren's and Ledderhose and that when they stopped the diet it seemed to get worse. 

The IGF-2 link:

There is some logic behind this, after all I have already discussed how these conditions can be linked to IGF2 and IGF1 is linked to calorie restriction. However further research did not seem to come up with any evidence to suggest a good link between IGF1 and collagen. The only way I could see that the IGF2 information could help is as follows: 

• I know that IGFBP6 binds to both IGF1 and IGF2, albeit more strongly to IGF2, and that calorie restriction causes a decrease in IGF1.

• So of you have less IGF1 then the IGFBP6 is more likely to bind to IGF2, assuming that the concentrations are at a level where the increased availability of IGFBP2 still results in an increased binding affinity for IGF2. 

• So if low IGF1 causes an increase in IGFBP6 binding to IGF2 and therefore decrease the downstream effects of IGF2 one of which is collagen production you may see a difference http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684083/figure/F3/

I think that the above is a little bit of a stretch but you never know. That was all I could find using IGF1 and collagen.

Figure 1: Overview of the impact of TGF-B1 on Collagen production and how calorie restriction impacting IGF-1 levels may result in a lowering of Collagen production.

Calorie Restriction and Collagen:

So instead of that I took a different approach and decided to look for a straight linked between calorie restriction and collagen. Here I managed to find a link, in that the following paper states that calorie restriction results in a decrease in collagen production, perhaps this would also hold true a) in humans b) under conditions where Dupuytren's is present. (Ref 1). I did not have full access to the paper so could not really see what they had done but it also states that this decreased collagen production also has a negative impact on would healing which of course relies, to some extent, on the same pathways as Dupuytren's. This may be a good thing for Dupuytren's or Ledderhose patients.  

The MMPs: 

Another key set of proteins in the extracellular matrix (ECM) is the MMP protein. These are involved in breaking things down and it has been shown that knock-down (removal in cells) of  MMP2 (Ref 2) inhibited cell mediated contraction. Interestingly there have been studies in rats that have shown that a calorierestricted diet results in a decrease in MMP2, so you could argue that a calorie restriction diet will lower MMP2 and that a lowered MMP2 will aid Dupuytren's and or Ledderhose. Furthermore they showed that it appears that calorie restriction also lowers the TGFB1 pathway which I discuss in the IGF2 link at the top. 

Figure 2: The role of MMP2 in Dupuytren's and the potential impact of calorie restriction on Dupuytren's and Collagen production. 

Collagen, the extra-cellular matrix and calorie restriction:

My final search I just thought I would have a look for ECM itself and calorie restriction and see what I could find and I found a couple of very interesting papers which I believe are both free to download. 

The first paper (Reference 4) is looking at the impact of calorie restriction in tumours. Interestingly they found that there was a decrease, as expected in IGF-1 which I have discussed above but they also observed that in calorie restricted mice there was a decrease in MMP2, which as discussed above is linked to the development of Dupuytren's. There was also a decrease in the levels of TGFB-1 which again I have also discussed above. 

Another protein that they mentioned that took my interested was collagen 4. Although Collagen 3 is the main component of the Dupuytren's lumps it is interesting that there are downstream effects on the levels of a collagen type. The second paper I am not going to go into as it basically has similar but less information as in the above paper though it does have a good picture on page 6 (Reference 5). 

The other side of the argument: 

You cannot construct a complete article without looking at both sides of the story. My research into this side was not as extensive because it is hard to find information disproving something that it just an idea but did bring up some interesting points.

The following paper (Ref 6) shows that despite the information I have seen above that TGF-B2 (yes 2 not 1, still looking into this but from what I have seen so far 1 and 2 act through the same pathways) does not affect the collagen levels in Dupuytren's cultures. In fact I am not sure what else to say on this side, if anyone has any information they would like to add then let me know.

Conclusions: 

Would having a calorie restricted diet hurt someone? It might but at the same time you can come off of it and may not have lost anything but you may have gained the used of your foot or stopped your hand from progressing. There is no information out there that says that it will work like that, in fact there is no direct evidence at all linking calorie restriction and Dupuytren's (for or against). The above data is a collection of the information that I could find that linked calorie restriction to pathways that have been linked to Dupuytren's. A lot of this data suggests that there could be some impact but there was nothing there that made me think that it definitely will work. 

As a non-medical professional I cannot endorse having a low calorie diet in general or a as a treatment for these conditions, although the information above suggests that it may have some impact. Note that many of the above studies were in cells or cancer and not in humans and none were related directly to Dupuytren's or related conditions. You should always consult a doctor before starting a very low calorie diet. If a doctor was interested in using this then I would be happy to work with them to look into this.

If any patients have experience of this and would like to share their story it would be great to add the information to the blog.

Other areas of interest: 

There is another signalling pathway called the Wnt signalling pathway. I know from back in my degree that this is using is development and it is still active in adults. I mention this pathway because it has been shown that a high number of Dupuytren's patients have SNPs (differences to everyone else) in genes that are associated with that patients (Ref 7). Although this is as far as the evidence go the Wnt signalling pathway has been linked to diabetes, cell growth and certainly warrants more investigation. 

Reference 1:

Reiser K1, McGee C, Rucker R, McDonald R - 

Access 29-09-2014

J Gerontol A Biol Sci Med Sci. 1995 Jan;50A(1):B40-7.Effects of aging and caloric restriction on extracellular matrix biosynthesis in a model of injury repair in rats.

http://www.ncbi.nlm.nih.gov/pubmed/7814778

Reference 2: 

Biochim Biophys Acta. 2012 Jun;1822(6):897-905. doi: 10.1016/j.bbadis.2012.02.001. Epub 2012 Feb 9. MMP-14 and MMP-2 are key metalloproteases in Dupuytren's disease fibroblast-mediated contraction.

Wilkinson JM1, Davidson RK, Swingler TE, Jones ER, Corps AN, Johnston P, Riley GP, Chojnowski AJ, Clark IM.

http://www.ncbi.nlm.nih.gov/pubmed/22342364

Reference 3: 

Calorie Restriction Reduces MMP-2 Activity and Retards Age-associated Aortic Restructuring in Rats , Mingyi Wang et al

http://circ.ahajournals.org/cgi/content/meeting_abstract/114/18_MeetingAbstracts/II_335-b

Reference 4:

Caloric restriction reduces growth of mammary tumors and metastases - Mariana S. De Lorenzo et al

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165123/

Reference 5: 

Molecular Mechanisms of Calorie Restriction’s Protection against Age-related Sclerosis, Elena Chiarpotto et al - http://onlinelibrary.wiley.com/doi/10.1080/15216540601106365/pdf

Reference 6: 

Enhanced Dupuytren's disease fibroblast populated collagen lattice contraction is independent of endogenous active TGF-β₂ Raymond Tse¹⁴, Jeffrey Howard¹²⁴, Yan Wu¹⁴ and Bing Siang Gan^1234*

http://www.biomedcentral.com/1471-2474/5/41

Reference 7: 

Wnt Signaling and Dupuytren's Disease, Guido H. Dolmans,  et al

http://www.nejm.org/doi/full/10.1056/NEJMoa1101029

Interview: Ledderhose surgery patient from Ohio

Today I have a patient interview with a Surgery patient from the States. 

1) Where are you from? 

I am from Ohio USA

2) Do you have Ledderhose and Dupuytren's?, How long have you had them? 

I am a 49 year old woman and I have both Ledderhose and Dupuytren's. I have Ledderhose on both feet. I have had Ledderhose since I was an infant. My Mother first noticed the nodule on my left foot when I was less than a year old. She doesn't remember more specifically how old I was. So in answer to the question I have had Ledderhose for 48 years. It wasn't until much later that I noticed the nodule on the right foot. I have only had that one for about 8 years. I have only had Dupuytren's for about 6 years.

3) Do you have a family history of this condition? 

As far as I can find I have Absolutely NO family history.

4) How did you find the medical awareness of these conditions? 

Most of what I know about both conditions I have learned on the internet. The surgeon that removed the first nodule is the one that told me what it was called. I didn't get much information from him but I was only 16 and don't really remember much detail from the experience.

5) You had surgery, were you made aware of the risks of having this?

Yes, I have had surgery twice on the left foot. I was only told that it could come back. I was not told much else.

6) What condition were you in when you had the surgery? 

Looking back, I wasn't in bad condition at all. Knowing what I know now I would not have had the surgery then. The condition was stabilized and it had not grown for years. I was involved in things in high school that was most likely putting more stress on the foot and causing it to hurt more. 

7) Could you please describe the surgery process and recovery? 

The first time I had surgery (both surgeries were on the left foot) the incision was only about an inch long (twice the length of the nodule) and went across the width of the foot. They only removed the nodule and the surgery only took about 40 minutes. The time on crutches after the surgery was about 2 weeks. The second surgery was was about 5 years later and the foot had become very painful. Mostly because of the scar tissue from the first surgery but I also had a new nodule. The incision for that surgery was lengthwise of the foot and was approximately 5 inches in length and slightly curved in an "S" shape. They removed the new nodule that was about the same size as the first one. They also removed scar tissue about 1 1/2 x 1 x 1/4 inches. The surgery took about 70 minutes and had the same recovery period of 2 weeks on crutches.

8) How successful would you say the surgery has been? 

I am convinced that the first surgery only made things worse. I am also glad I had the second because I am sure if the nodule grew much more I would not have been able to be on my feet much at all. The second surgery didn't result in the large scar tissue formation like the first. Although in the 26 years since the second surgery I have another nodule and it is twice the size of the ones removed. 

9) What other treatment options are you looking into?

I am very interested in the Radiotherapy that has been discussed. I would like to know more about it and where it is offered in the United States. 

9) Is there anything else you would like to share with the patient community?

Picture on the left is the left foot. This is the one I have had two surgeries on. This nodule is about  26 years old. Picture on the right is the right foot. No surgeries. Nodule is about 8 years old.

Picture on the left is left hand. Not as noticeable since the nodules aren't as large as the foot but you can see that I have a pit of some sort. 

The picture on the right is also the left hand but the hand is turned sideways so you can see a bit more of how large the area is. The first nodule in the hand was noticed 5 years ago. Thankfully the right hand seems to be free of any nodules at this time.

Interview with Aaron Wolfson, Radiotherapy specialist in Florida

Today I have an interview with Dr Aaron Wolfson from Florida. He uses radiotherapy to treat Dupuytren's and recently Ledderhose. I came across him when a patient I am in contact with was looking for a doctor in Florida and another patient I am in contact with is the patient they mention below. He seems happy with the way that he has been treated and said that the doctor I have interview here follows Dr Shaffer, that can only be a good thing. 

Aaron H. Wolfson, MD, FACR

Professor

Department of Radiation Oncology

University of Miami Miller School of Medicine

1475 NW 12th Avenue, D-31

Miami, FL 33136

Phone: (305) 243-4210

Fax: (305) 243-4363
To see this address On a map 

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

    I have been interested in treating patients with benign fibroblastic diseases (such as desmoids tumors, meningiomas, heterotopic bone, keloids etc) for over 20 years. I have only become interested in treating patients with Dupuytren’s and Ledderhose disease for the past three years. So far I have done four consults and one patient has accepted treatment (currently on a break).

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

    See above. The patient has Ledderhose disease.

3) How common do you think Dupuytren's and Ledderhose are in the USA? They are supposedly more common in males then females and have been linked to smoking, alcohol consumption and diabetes are these risk factors you see in your patients? 

I actually don’t know the answer to this question. I get about three to four calls a year from all over the U.S. for the past three years. You are correct about the risk factors and most I have encountered have more than one usually.

4) Roughly what percentage of the patients you have treated have had a family history of these diseases? 

    The patient I am currently treating has a family member with this disease.

5) You treat with radiotherapy, what protocol do you use (dose, no of doses and gap between the 2 weeks of treatment etc.) and what is the success rate on these diseases with radiotherapy? 

     I use the regimen proposed by Dr. M.H. Seegenschmiedt of Essen, Germany in  which the patient receives once electron beam treatment to the region a day for 5 work days followed by an 8 to 10 week break at which time the patient receives an additional 5 daily treatments (3 Gy per fraction x 10 fractions in total = 30 Gy).

6) Why is radiotherapy a better course of action than other treatments such as surgery? 

    The data from dr. Seegenschmiedt show only about a 10% progression rate with radiation therapy with up to about 50% progression rate with surgery.

7) What are your thoughts on other treatments that are becoming available such as Xiapex? 

    I do not have any experience with Xiapex but I am sure more medications will become available.

8) Finally do you have any advice or other information that you would like to share with Dupuytren's / Ledderhose patients?

  My main advice is to have early detection of the disease in which it is in the nodule stage. It is very difficult to treat the disease in the cord stage.

Dupuytren Diathesis and Genetic Risk

I have been saying over my last couple of posts that there is a paper that I would like to cover but I could not get access to it. Well I have tried through all my normal channels and I am unable to view this paper with any of the accounts that I have. So as usual I am going to try and do the best job that I can from the information that I can get access to. 

The title of this paper is Dupuytren Diathesis and Genetic Risk authored by 

Guido H. Dolmans, MD^, , 

Geertruida H. de Bock, PhD, 

Paul M. Werker, MD, PhD from 

Departments of Plastic Surgery and Epidemiology, University Medical Center Groningen and University of Groningen, Groningen, the Netherlands published in the jounral of hand surgery. 

In this paper they are looking at various different SNPs that have been associated with Dupuytren's. SNPs are individual changes in the DNA code so for example in a specific part of the DNA code one person may have AAAA and another may have AAAT and this change may be associated with certain disease etc. In this paper they have a set of 9 of these changes that they are looking at as they have been link to DD and to see whether they are linked to certain clinical characteristics such as the manner of the DD and I believe other things such as Ledderhose. 

They use a large pool of patients (over 1000) and score each of these for their genetic risk based on the 9 SNPs mentioned above. What they showed from this was that patients that had onset below 50 years old, a family history of DD, knuckle pads and Ledderhose all showed up in the high genetic risk group. The actual wording is not clear but I am guessing due to the number of patients that it is if you have any of the above and DD then you are likely to fall into the high genetic score group. I am hoping that as I only have LD below the age of 50 that I do not have a high genetic predisposition. 

Other than that I am not able to tell a whole lot from the information that is freely available.

There should be another post on the way tomorrow or Tuesday so make sure to stay tuned :-)

Interview with JHB, LD, DD patient had radiotherapy and Xiapex

In this interview I am talking too a patient who had both Ledderhose and Dupuytren's and has experience with different kinds of treatments. 

1) Do you have Dupuytren's disease, Ledderhose disease or both? 

I have both Dupuytren's and Ledderhose disease. I have had Dup in my left hand for years. I got LD in both feet about 2 years ago.

2) Do you have any family history of the disease? 

No, so far as I can tell no one in my family has had either Dup nor LD

3) what treatments have you had for your diseases? 

I had radiotherapy on the feet and hand in 2010. It has slowed the LD but the Dup was too far advanced in my hand. Since I had the RT a large nodule has appeared in my right arch but fortunately it isn't painful. I had the radiotherapy done in Wimbledon, UK, under the guidance of Dr John Glees.  I had 10 sessions over 2 months. I didn't notice any real improvement for a month or two when I realised that the nodules on my left foot had stopped hurting. I really think it only works at all in the very early stages and even then it possibly only slows the development down. 

I had Xiapex in the hand in November last year to straighten my middle and little finger. The results were good but I do need to stretch the fingers every day to stop the fingers resuming their previous curl.

4) For you it sounds like both radiotherapy and Xiapex have been successful, what were your motivations behind trying them? 

I wanted to avoid surgery as it can only be repeated once or twice and I am only in my early 50's.

5) I know from talking with you that you would like a trial for Xiapex in the feet, why is that? 

The reason I think Xiapex may be the answer for LD is that the nodules in my palm and fingers have shrunk and softened. A big nodule in my palm used to hurt when i gripped things but the pain has now gone. If it has greatly reduced the nodules in my hand why not the feet? It must be worth a trial.

6) I know you are not a Dupuytren's specialist but if you met someone with Dupuytren's what treatment would you recommend? Of course I appreciate that this may vary depending on the stage of the disease

For Dup I would suggest a needle procedure for anyone who works with their hands and Xiapex for everyone else as it takes longer to heal with Xiapex. If it's really bad then surgery has to be considered. Radiotherapy is only worth considering in the early stages of the disease (before there is too much contracture.

Forget creams and potions; they don't work.

7) How much pain / discomfort are you find is caused by the Dupuytren's and Ledderhose and have you found anything that helps to alleviate any problems?

I get cramp and some stiffness in the hand. There is no pain in my feet as the nodules on my left foot stopped hurting after the RT, but they are still the same size.

Whilst chatting with him one of the comments that I can't place under a specific question but would like to include is something which I agree strongly with him about and that is: 

"The problem is that Ledderhose is awful but so rare that the NHS isn't nearly so concerned about it as they are Dupuytren's." 

This was a good interview as John has experienced many different kinds of treatments and this is one thing that I am particularly interested in covering. It was also good to hear from someone who has had radiotherapy for the Ledderhose on their feet and although there is no decrease in size of the nodules there has been a decrease in pain which is something that I too hope to experience. 

John also has a big interest in Dupuytren's and Ledderhose and the care and treatments that students receive. In particular I was interested by his enthusiasm for Xiapex as a treatment for Ledderhose as well as Dupuytren's. This is something which I am sure many Ledderhose patients would love to try, no surgery, no increased cancer risk and potentially a big gain. I know that the theory says that the collaganase that makes up Xiapex is mainly aimed at Dupuytren's because of the collagen type that the nodules are composed of is different to that of the cords. But here he has experienced an improvement in his Dupuytren's nodules after treatment with Xiapex and I agree with his sentiment of why not try it? My guess, money. 

It's in your hands - Dupuytren's

Ok so as I promised I am going to have a look at a thing from 

Pfizer called "it is in your hands". 

There reason that I am looking at this is of course because Dupuytren's is related to Ledderhose and things that help that might be able to help this. Why are Pfizer involved? Well of course this is because they have the rights behind Xiaflex/Xiapex which is a collagenase injection that can be used to help break down the cords in Dupuytren's Contracture and therefore help to restore normal function of the hand. I have covered it a little bit previously in this post here - Xiaflex in cells. 

So what is in your hands??? 

This is the logo that Pfizer are using, all rights are theirs of course and I am putting it here to promote their site. Though I do not have any affiliation to them or anything like that.  

Well Pfizer are on a mission to try and raise awareness of Dupuytren's and as such there is the website - Dupuytren's Disease - It is in your hands which has some information on Dupuytren's disease. Of course this does include treatment options and to be fair there is a good deal of information there however under non-surgical options they are of course putting Collagenase injections as the best choice. 

They also have a stories section where they have video stories from a variety of patients with Dupuytren's disease and they discuss all of the different treatments options that they have had. This is really good to get out there and hopefully it will help patients in the future. 

They also have a very useful FAQ and a useful links bit where they link to the International Dupuytren's Society. 

So I guess this site is useful for anyone with Dupuytren's or indeed anyone looking to find out more about Dupuytren's disease, it has lots of stories where you can learn how people are coping with it and what they have gone through but at no stage is there any mention of Ledderhose disease or peyronie's disease. Now I know that Xiaflex has not been shown to be useful but surely under the FAQ they could have it has something to look out for. I think the fact they have not mention them is a disgrace as awareness of Ledderhose and peyronie's disease is probably less than Dupuytren's and what harm would it do to stick it in there? Anyway it is a good site and does have lots of good info. 

I actually find the omission of peyronie's disease particularly odd given that this morning I also got a news alert through Google Scholar saying that there is a new paper coming out on the use of Collagenase injections for the treatment of peyronie's disease. The abstract can be found here Sexual dysfunction: C. histolyticum collagenase effective against Peyronie

So as part of this scheme they have also released a bunch of videos which are all available on YouTube, but you can not make comments so not linking to here or complaining about the lack of any mention of Ledderhose disease. 

Videos: 

I am just going to embed one of these videos but I urge you to visit YouTube and view some more of them as they are very interesting and hopefully will help to raise awareness. 

I think that the collection of videos really do help to increase the amount of understanding that some people might have into not only Dupuytren's as a whole but the way in which it can change everyday life. I do think that they could be better, they do only look at one person and from what I can see there is only proper contracture in one finger, the little finger, but I might be wrong. 

Summary: 

Hopefully all of this helps people to know about Dupuytren's and maybe if they know about Dupuytren's then they might begin to learn about Ledderhose. Maybe this will help gain money for research into these diseases that might one day offer a cure and I am sure the this is something that not only the patients but hopefully also the likes of Pfizer are interested in. 

An interesting read on Dupuytren's contracture

I came across this yesterday and thought it was a very interesting read on Dupuytren's http://www.dupuytrens.me.uk/dupuytrens.html

To quote their title...

I am not going to copy what they have said because well that would just be copying but I am going to look through it and try and pick out some key points, unfortunately as far as I can tell the author has left no contact details so I can't get hold of them to ask them some questions or even whether they mind me posting about their story which is why I am going to try and do my best and try and draw things from their experience rather than copy their information (a lot of which I already have here on the blog anyway). In fact I just urge you to read it and I am only going to give a summary below to hopefully get you interested. A lot of time and effort has clearly gone into this one long post and it is almost a bit like my blog all chucked out in one go. 

Summary: 

Male that has Dupuytren's in both hands. He had both hands operated on by different surgeons at different times, the hand operated on later had recurring Dupuytren's and this person thinks it is the fault of the Surgeon. They go on to talk in depth not only about their experience but about the hand, Dupuytren's, Collagen, Fibroblasts, growth factors and some of the alternative treatments, any of that sound familiar?