Kristen Highland, MD, Director of The Rheumatic Lung Disease Program at The Cleveland Clinic, talks about the first FDA approved drug ever for Scleroderma interstitial lung disease
Can you explain what scleroderma is and what these patients go through?
Scleroderma comes from the root word sclero meaning hardening and Derma meaning of the skin. The classic manifestation of Scleroderma is patients notice skin thickening, but Scleroderma can also affect the internal organs very frequently. The lung can affect the heart, the kidneys, muscles, many internal manifestations. The Sophos is another, another big one. So, often a patient’s first symptom is that they notice that they are developing Reno’s phenomenon. This is where the fingers will turn colors if they get cold or sometimes with vibration. Peep at a patient who operated Jackhammer or another patient that did a lot of typing. It can cause the fingers to turn colors like blue or sometimes white, then, as they warm up, red, and that can be very uncomfortable sometimes as the fingers don’t get enough blood supply. They can also get very painful ulcers on the fingertips. Those are often the very first symptoms of scleroderma, generally followed by a lot of gastrointestinal reflux. So, patients are complaining usually of heartburn and indigestion and they’re still not necessarily putting the pieces together. Then eventually, most patients develop some skin manifestations. There are two types of scleroderma. One is called limited cutaneous systemic sclerosis, which means the skin involvement is generally below the elbows, below the knees, or also can be on the neck and face versus diffuse cutaneous systemic sclerosis where the skin involvement can be on the trunk and proximal to the knees and elbows. Then early on in scleroderma, we say systemic sclerosis instead of Scleroderma because of the internal organ involvement as a systemic disease. So early on is when we see patients developing their interstitial lung disease or you know, we use the words pulmonary fibrosis or inflammation in the lungs. That tends to be an earlier manifestation that can lead to shortness of breath, significant cough. This leads to decreased exercise tolerance, which affects patient’s quality of life down the road in scleroderma, often eight to 10 years out, patients can develop pulmonary hypertension or the pulmonary materials in the lungs get thickened and narrowed, and that causes resistance in the lungs, which puts a stress on the right side of the heart. So there are several different pulmonary manifestations and then, of course, we always worry about the kidneys and the heart, muscles, and joints and things like that too. It can be a very painful disease. Patients generally have a lot of fatigue and a lot of pain. The skin involvement can be very painful, I had one patient who had such bad skin involvement she didn’t even want to have her blood pressure taken– She couldn’t tolerate it. Sometimes the skin is very itchy, they can have arthritis and muscle complaints, they’re very uncomfortable, very fatigued.
So, what’s the treatment right now?
For Scleroderma as a complete disease, we don’t have a treatment. We do have our very first FDA approved drug ever for Scleroderma interstitial lung disease and that drug is called nintedanib, which is the anti-fibrotic. Can you say that three times fast? Generally, when we try to treat scleroderma, we are treating the specific organ manifestation and we steal data and experience from other rheumatologic diseases. There have been some guidelines on treatment approaches for the different manifestations of scleroderma. The European league against rheumatism has recommended for severe skin disease to consider methotrexate, which is a drug commonly used in rheumatoid arthritis. For lung disease generally, the recommendation is immunosuppressive therapy and there have been two big trials using immunosuppressive therapies and scleroderma. One looked at cyclophosphamide, which is a pretty toxic chemotherapy agent, and that showed to have a modest effect or improvement on lung function. But because it’s associated with toxicity, the Scleroderma lung study looked at an alternative drug and that was mycophenolate, which showed similar efficacy to the cyclophosphamide. But we know that there are multiple pathways involved in scleroderma, there’s the immunologic pathway, so, therefore, immunosuppressive therapies might be beneficial. Then there’s the fibrotic pathway. The last really big trial in Scleroderma interstitial lung disease was looking at Nintedanib and some of those patients were on background mycophenolate. So, it looks like there may be a role for both in immunosuppressive therapy and anti-fibrotic therapy, at least as it pertains to the lung.
What does it do for the lung?
If you take a fibroblast, which is a fibrotic cell put on a normal lung cell, it will make that normal lung cell turn into a fibroblast. So, we know fibrosis causes fibrosis. Nintedanib is an anti-fibrotic drug to stop that fibrotic process. It protects the norms. It can protect the normal cell.
So, it doesn’t make things go away?
Unfortunately, nothing makes things go away in scleroderma. In fact, the father of American rheumatology once said, “no drug has truly failed until it’s been tried in scleroderma.” But I think we’re now starting to see some hope in scleroderma, with these different trials. So, if that means it slows the progression, then it slows the progression, which then extends people’s survival, extends people’s independence. This is really important because Scleroderma often is the disease of sort of younger women, age 30 to 50 women, so, they have a lot of years left to live and they want to live those years.
So, if we can at least halt the progression or doing a good job in diagnosis, what is the survival rate?
It’s really variable depending on the internal organ involvement. So, it’s really hard to put a finger on that. The diagnosis and prognosis or the prognostic conversations really need to be individualized depending on what organ involvement there is.
Can you tell me a little bit about Lynn?
So, Lynn came to me for a second opinion and really represented how a lot of my patients struggle with actually getting their diagnosis. She had been to a variety of doctors, with a variety of complaints including cough and shortness of breath. When I saw her, I was able to put the pieces together, probably the help of my training in Rheumatology as well and I realize that her underlying diagnosis was scleroderma. She had very puffy fingers. She had raid nose phenomenon. I think she may have had a digital ulcer. She had a few funny looking blood vessels at the surface of the skin. She had evidence of interstitial lung disease in a pattern that would make you think of a potential rheumatologic disease. And that pattern on the chest CT scan is what we call nonspecific interstitial pneumonia, which has a different pattern than someone with idiopathic pulmonary fibrosis. Then we ordered some blood work, which showed that she had typical autoantibodies that were associated with Scleroderma. So, we put her on mycophenolate, based on data from the Scleroderma lung studies. She actually had some immediate improvement in both her pulmonary function testing and some of her extrapulmonary symptoms. We also treated her aggressively for acid reflux and we’re incredibly grateful she was willing to participate in the census study, which was the big study looking at Nintedanib. So, she was actually a patient in that study, and she was randomized to the active study drug. She actually got picked to be on Nintedanib and remains on a combination of Nintedanib and mycophenolate to this day. And yes, she actually is a little atypical in that she had a very good response. That combination of therapy with significant improvement in her lung function.
So, is your study finished?
The first part on the side of the census study is finished and the big results of that show there was more than a 40% decrease in the rate of forced vital capacity or lung function decline compared to the placebo. She’s participated in a census on which there is a continuation study. So, the census ended at one year and with the continuation study, we’re looking to see if these effects last longer than a year. So, she’s involved in that study as well. But we’re pretty excited because I think this is one of the first studies that truly brings hope to our patients with scleroderma.
Can you also tell us a little about Bob?
We think that he has some autoimmune features to his pulmonary fibrosis. His interstitial lung disease is a little bit uncharacterized, but probably best fits in this kind of new category called IPAF, and that stands for interstitial pneumonia with autoimmune features. He had an acute presentation of his interstitial lung disease. He actually almost died. He was in the ICU on a ventilator and he got a bunch of steroids and a bunch of immunosuppressive therapy and had enough improvement that he was able to get out of the ICU and into a regular bed and his oxygen requirements went way down. So, he definitely has fibrosis and so his lung disease is chronic and has very fibrotic changes on his chest. CT scans show his lung function has more or less plateaued with a combination of immunosuppressive therapy. Most recently we added Nintedanib to his regimen because of this belief in the anti-fibrotic pathways. There was a study, shortly after the census study was published, called the inbuilt study, which was a study that kind of looked at all corners of interstitial lung disease and if they had evidence of progression. So, people with interstitial lung disease were declining despite whatever they were being treated with. So progressive fibrosis, those patients were treated with Nintedanib and in that study, there was more than a 60% reduction in the rate of forced vital capacity decline. Now, we should also be considering anti-fibrotic therapies in patients with progressive interstitial lung disease regardless of the type of interstitial lung disease. So, this is all data that is kind of building from the initial studies in idiopathic pulmonary fibrosis. Then we have Scleroderma and this progress of interstitial lung disease phenotype. I think when we look at interstitial lung disease as a whole there’s some component of inflammation. In some diseases, it might be a whole lot and in other diseases might be just a tiny bit and then some with a co-component of fibrosis. So, kind of how much of each component is there, is what we need to figure out as we’re choosing therapies to treat our patients.
For you, this has to be exciting because like you said, there’s not a lot of treatment.
It is really exciting. I feel like there is a new era in interstitial lung disease and somewhat of a paradigm shift as we’re starting to approach these patients.
Are there any risks or side effects of this drug?
Certainly. All drugs have side effects. Obviously, immunosuppressive therapies can make you prone to infections. Both Nintedanib and the other anti-fibrotic, which is called pirfenidone, have significant gastrointestinal side effects. pirfenidone tends to have more nausea and gastrointestinal reflux. Whereas Nintedanib often has a lot of diarrhea associated with it. It can also sometimes raise the outcome of liver function tests. Those are things we monitor with both drugs. The side effects are often manageable with a proactive approach but sometimes these strokes are difficult to tolerate for our patients.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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