07/09/2022
We have received many enquiries about whether Dr Tomlinson will inject the medication used in a recent trial published in The Lancet into the hands of individuals who have Dupuytren’s disease. This post gives an excellent explanation of the current state of play, and the reasons why these injections are not provided on demand.
Disease Modifying AntiDupuytren Drugs
The path to a Dupuytren cure is connected to the story of drugs for rheumatoid arthritis. The evolution of rheumatoid drug treatment dates back centuries, based on guesswork and trial and error. During this time, hundreds of rheumatoid "cures" were recommended - herbs, diets, bedrest, baths, special clothing, radioactive exposure, special jewelry, injections of arsenic or copper, bee venom, electroconvulsive therapy, standing inside the carcass of a beached whale (!), treatments to promote jaundice, spinal tap to remove and reinject spinal fluid, and many more. Each of these disappeared as evidence grew that they didn't work for most people. Complicating things, it's pretty common for the pain and inflammation of rheumatoid arthritis to stop without any treatment: did the person get better because of the treatment, or was improvement unrelated to the treatment? Over time, better treatments were developed: gold injections, cortisone, methotrexate, and others. These reduced inflammation and made people feel better but often didn't stop progressive joint damage from the disease. People felt better as their bodies got worse. Fortunately, this changed.
Rheumatoid frequently affects the hands. Early in my hand surgery practice, I often did reconstructive surgery for rheumatoid hand deformities on patients who had been on rheumatoid medicines for years. This surgery made dramatic improvements. Unfortunately, these improvements were lost over time if the disease remained active. Surgery was not a cure, but for many, it was the only option when medical treatment failed. Then there was a change. The steady stream of rheumatoid hand patients referred to me for surgery slowed to a trickle. Not just for me but for my colleagues across the country. Why? Because finally, finally, a drug became available to treat the specific biology of rheumatoid, one that prevented progressive hand deformities. That first drug was etanercept, marketed as Enbrel. This change was possible because of the discovery of the role of TNF, a key molecule in rheumatoid. Enbrel was developed to inactivate this specific molecule.
Drugs that work on rheumatoid biology are called Disease-Modifying Antirheumatic Drugs, or DMARDs. Conventional DMARDs include cortisone, methotrexate, and others. They suppress some of the immune overactivity of rheumatoid but are not very specific. Biologic DMARDS like Enbrel target specific molecules. Using the analogy of a dripping faucet, conventional DMARDS are like a mop, but biological DMARDS turn off the tap. The change was miraculous - and the proof? Hand surgeons stopped doing almost any rheumatoid hand surgery. If you think surgeons push back against new treatments because they don't want to lose business, think again. Hand surgeons welcomed this new treatment and breathed a collective sigh of relief. I admit I enjoyed fixing the deformities, but I also enjoyed the technical challenge of expertly fixing a snarled 8-track tape. No one misses the way things were.
What does this have to do with Dupuytren? Quite a lot. First, Dupuytren is where rheumatoid was a century ago. No proven preventive treatments. Dupuytren progresses unpredictably and intermittently, and nodules sometimes go away without treatment. This makes it impossible to predict long-term outcomes based only on short-term treatment effects. Second, as with rheumatoid, surgery is not a cure for Dupuytren, and repeat surgery may have prohibitive risk. Third, like Dupuytren, rheumatoid has a strong genetic component, but genetic research has yet to lead to new treatments. Fourth, just like rheumatoid, if a new treatment eliminates the need for Dupuytren surgery, all hand surgeons will again breathe a sigh of relief. Fifth, progress with biologic DMARDS may apply to Dupuytren, opening the door to Disease Modifying AntiDupuytren Drugs or DMADDs. Dupuytren biology is complex, involving many target molecules. TNF is part of the picture, but its fundamental role and the roles of other Dupuytren-related molecules remain to be seen.
It costs up to a billion dollars to bring a new drug to market, but it costs much less to repurpose and approve an existing drug for a new indication. The hope is to find an existing drug that can also be used to treat Dupuytren. For example, these FDA-approved drugs might be repurposed as DMADDs.
- Disclaimer - This is a research snapshot, not medical advice.
Adalimumab (Humira®), injectable, TNF blocker. Approved for rheumatoid and related disorders. In clinical trials as an injection treatment for Dupuytren nodules. https://pubmed.ncbi.nlm.nih.gov/35949922/
Pirfenidone (Esbriet®), oral, exact mechanism unknown. Approved for pulmonary fibrosis. No Dupuytren clinical trials yet. https://pubmed.ncbi.nlm.nih.gov/30927912/
Sorafenib (Nexavar®), oral, kinase inhibitor. Approved for certain advanced cancers of the kidney, liver, or thyroid. Off-label use was reported for Dupuytren and Ledderhose. https://pubmed.ncbi.nlm.nih.gov/35274715/
Tofacitinib (Xeljanz®), oral, JAK/STAT inhibitor. Approved for rheumatoid and related disorders. Laboratory studies suggest potential off-label Dupuytren use. https://pubmed.ncbi.nlm.nih.gov/32695877/
Ruxolitinib (Opzelura™), topical cream or oral, JAK inhibitor. Approved for some types of myelofibrosis, eczema, and vitiligo. Bioinformatics suggests possible off-label use for Dupuytren. https://pubmed.ncbi.nlm.nih.gov/33826640/
Imatinib (Gleevec®), oral, tyrosine kinase receptor inhibitor. Approved for hematologic and other malignancies. Cell culture research suggests potential off-label Dupuytren use. https://pubmed.ncbi.nlm.nih.gov/21711521/
Niclosamide (generic), oral, exact mechanism unknown. Approved for treating tapeworm infections. Research suggesting use in fibrotic diseases of liver https://pubmed.ncbi.nlm.nih.gov/34966659/ and lung https://pubmed.ncbi.nlm.nih.gov/35159160/, which have some biological overlap with Dupuytren-related pathways.
Verteporfin (Visudyne®), intravenous injection, exact mechanism unknown. Approved for the treatment of macular degeneration. https://pubmed.ncbi.nlm.nih.gov/35977978/
It's encouraging to have a list this long, and there are many other potential drugs. It's impressive that drugs used for a wide range of benign and malignant diseases might also help Dupuytren, but that is how nature works - all biological molecules do many things. For example, aspirin reduces inflammation, but also thins the blood, and may help prevent colorectal cancer.
So why isn't everyone using these drugs on Dupuytren today?
Side effects. All biological molecules do many things. Even drugs targeting one specific molecule can have many unexpected consequences. For example, some drugs on this list affect the immune system, which carries its own risks, particularly with long-term treatment.
Cost. Off-label use is often not covered by medical insurance, and most of the drugs on the list are expensive.
Long-term effectiveness. Dupuytren is a chronic condition. Short-term gains may not persist and may not predict long-term improvement. This is the elephant in the room for current treatments. Just like surgery for rheumatoid deformities, procedures for Dupuytren deformities work in the short term but often fail in the long term. The same can be true for drugs.
How can we learn how well any of these drugs work in the long term? This is where the Dupuytren and rheumatoid paths diverge in two important ways.
Measurements. There are standard rheumatoid blood tests to diagnose, stage, and measure biological response to treatment. No such tests yet exist for Dupuytren because we don't yet know which blood molecules are abnormal in Dupuytren. Without a blood test, the only way to measure Dupuytren drug effects is by physical examination - a major obstacle to proving drug effectiveness.
Timelines. On average, rheumatoid progresses more rapidly and dramatically than Dupuytren - weeks to months compared to years for Dupuytren. The longer it takes a disease to damage the body, the more difficult it is to measure the effects of preventive treatment. If Dupuytren progresses from nodule to contracture (thankfully, it doesn't always), it takes an average of eight years to go from the initial diagnosis to the first corrective procedure. Without a blood test, the only way to measure the preventive effect of drugs on early disease is a large, long, expensive research study for each drug.
The answer to these issues, the path to transform Dupuytren treatment is to develop a Dupuytren blood test - a liquid biopsy. The first step is to learn which blood molecules are abnormal in Dupuytren. The Dupuytren Research Group is conducting blood biomarker discovery research right now to answer this exact question. Contact the Dupuytren Research Group to learn how you can help.
Thanks!
Charles Eaton MD
