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Dupuytren and Rare Disease Research

Is Dupuytren disease common or rare?

I recently attended the Rare Drug Development Symposium in Philadelphia. Why? Is Dupuytren really a rare disease? Yes and no. Mild Dupuytren is common but very severe Dupuytren is rare – in the same way that cats are common but chimeric cats with crazy colors are rare.

What does “mild” or “severe” Dupuytren really mean? People usually think of severity as severely bent fingers. While it’s true that fingers that are very bent don’t function as well and are less likely to be made straight with treatment, the more important factor is biologic severity. Biologically severe Dupuytren is prone to recurrence after treatment regardless of how bent the fingers are or the type of treatment. Biologically severe Dupuytren is also called treatment-resistant Dupuytren. It’s more likely when a person’s story has certain details: young when diagnosed, a parent or sibling with Dupuytren, disease outside the palm such as knuckle pads or Ledderhose. These details are called “Dupuytren diathesis factors“. They’re not perfect predictors. Some people with diathesis factors have mild Dupuytren. Some with no diathesis factors have terrible problems with Dupuytren recurrence. Right now, there’s no sure way to tell whether someone has treatment-resistant Dupuytren until after treatment. Retreatment for recurrence is the real elephant in the room. The problem with retreatment is that it is progressively less effective and riskier. One in four people who have had three open Dupuytren surgeries on the same finger will have suffered a permanent surgical complication along the way.

Overall, Dupuytren is common, affecting ten million Americans and millions more worldwide. Most people with Dupuytren have a mild version. They may have a lump or a slight finger bend as the only issue of their lifetime. They might have one finger affected, have a successful procedure, and never another problem. At any one time, four out of five people with Dupuytren only have a lump in their palm or a slightly bent finger. Only one in five people with Dupuytren have fingers bent enough to even consider treatment.

The severe version of Dupuytren isn’t common. Only a few percent of people with Dupuytren – a few hundred thousand Americans – have severe treatment-resistant disease. Severe Dupuytren is considered a rare disease, and because there is no effective long-term treatment it’s also classified as an orphan disease. This is why it makes sense to explore rare disease research tools to develop better Dupuytren treatments.

A common obstacle in rare disease treatment research is a lack of understanding of the root biology, not knowing where to start even if it’s clearly a genetic issue. This is true for Dupuytren. Clues to Dupuytren biology are scattered across systems involved in immune mechanisms, inflammation, effects of aging, gender, injury, and normal body maintenance. For Dupuytren, stumbling across an effective biological treatment through blind trial and error is unlikely, as the last 200 years of failure have shown. Recognizing this problem is the first step in moving past it.

Which leads to this: I bring good news from the Rare Drug Development Symposium. Even if we don’t currently understand the complete biology of Dupuytren, there is a possible way to identify existing drugs which might also work on Dupuytren disease. Most drugs have a variety of effects on different areas of biology. What we call these effects depends on context and marketing. If a drug effect helps a disease, it’s called a therapeutic effect. If it does something else, it’s called a side effect. Sometimes what’s first considered a side effect of a drug is more valuable than the original use. This is the path that repurposed aspirin from anti-inflammatory to blood thinner, thalidomide from sleeping pill to the treatment of leprosy and multiple myeloma, and sildenafil from blood pressure medicine to Viagra. The process of using a side effect of an existing drug to treat a different disease altogether is called drug repurposing or repositioning.

There were several examples of drug repurposing given at the Rare Drug Development Symposium. Most impressive was how to find unexpected drug candidates to repurpose. The traditional approach to finding drugs is to compare what’s known about the cause and effect biology of a disease with a class of drugs known to act on this biology. The symposium demonstrated a fascinatingly different approach for drug discovery. Rather than waiting to understand all of the biologies of a disease, researchers used brute-force computer analysis. Researchers gathered all gene and protein related tests of a disease, whether or not they were thought to contribute directly to the disease. They compared this data with a database of all known molecular effects of over 13,000 drugs – whether or not they were thought to act on this disease. They then studied the list of matches and why they matched. In one case this approach matched a rare treatment-resistant pediatric brain tumor with a 250-year old heart drug, now being tested to improve outcomes.

This approach dovetails perfectly with the Dupuytren Research Group International Dupuytren Data Bank (IDDB). The core cause-and-effect biology of Dupuytren is still not known. Our upcoming pilot study will collect gene and protein data to develop a blood test to measure the response to drug treatment. At the same time, this same data can be used to search for existing drugs to repurpose for Dupuytren disease. We are clearly on the fastest logical path to a breakthrough in Dupuytren care.

Charles Eaton MD