Diagnosis and Management of Systemic Sclerosis

Kristin Highland, MD, provides an overview of systemic sclerosis and associated interstitial lung disease, including symptoms and diagnosis, who's at risk, and new and upcoming treatments for this complex disease.

Kristin Highland, MD, is a pulmonary critical care physician and rheumatologist who serves as director of the Rheumatic Lung Disease Program at the Cleveland Clinic in Cleveland, Ohio.



Dr Kristin Highland: Hi, my name is Kristin Highland. I am a pulmonary/critical care physician. I'm also board‑certified in rheumatology. I'm Director of the Rheumatic Lung Disease Program at the Cleveland Clinic in Cleveland, Ohio.

Rebecca Mashaw: Thank you for joining us today, Dr. Highland. It's good to have you here to talk about this very complex disease. Let's start off with the basics. Can you give us a brief overview of what systemic sclerosis is, and the different presentations that you see?

Dr Highland: Absolutely. This is a rheumatologic disease, or an autoimmune disease. That means that the body is attacking itself. Some people call this a connective tissue disease. There are two types of scleroderma.

There's localized scleroderma, which is confined to the skin, and then there's systemic sclerosis, which has skin involvement as well as internal organ involvement. Systemic sclerosis has a number of variants. There is limited cutaneous systemic sclerosis, which is skin involvement that is limited to below the elbows, below the knees, and can involve the face and neck, versus diffuse cutaneous systemic sclerosis, where there's more skin involvement— above the knees and above the elbows, it can be on the trunk and on the abdomen and the chest.

There's a variant called systemic sclerosis sine scleroderma. These are people who have the characteristic internal organ involvement, the characteristic antibodies that go with the disease, but they don't have the skin involvement.

RM: This is a very complicated disease and it sounds like it could be an enormous diagnostic challenge.

Dr Highland: Absolutely. Part of the problem is that the patients without the typical skin involvement are often presenting to a pulmonologist, for instance, for interstitial lung disease. Is this idiopathic pulmonary fibrosis? Without a heightened sense of curiosity by the pulmonologist, you might miss those subtle features of scleroderma. To add an extra layer of complexity, is that these rheumatologic diseases often overlap.

Sometimes, patients have joint pain and they get labeled rheumatoid arthritis, or they have some features of rheumatoid arthritis plus some scleroderma, or very commonly, features of lupus or features of polymyositis or dermatomyositis where they have some muscle involvement. Then, you're almost not sure what rheumatologic disease you're treating.

RM: Who's most likely to develop systemic sclerosis, whichever presentation it comes as?

Dr Highland: It's more common in females, as is most of our autoimmune conditions. It tends to be a little more prevalent in African Americans. Generally occurs within the fourth to fifth decade of life.

The greatest prevalence, at least in the United States, of scleroderma is with the Choctaw. Within that Native American population, the prevalence of scleroderma is probably 300 times that of anywhere else in the world.

RM: What is the overall prevalence, say, in the United States?

Dr Highland: It's 1 to 2 per 100,000 patient population, is my recollection. It's not common. If you talk to the average community‑based rheumatologist, they can probably count their scleroderma patients on 1 or maybe 2 hands.

The diagnosis of scleroderma is based on a set of criteria that were redone or updated in 2013 by the European League Against Rheumatism and American College of Rheumatology.

With the exception of diffuse skin involvement, there is no one criteria that can give you the diagnosis of scleroderma. These criteria are a combination of fibrotic features, vascular features, and immunologic features.

You have to have 9 points to get your diagnosis of scleroderma. If you do have skin thickening that is above your knuckles ‑‑ the MCPs ‑‑ above your knuckles, that's enough so that you can have 1 criteria. If you only maybe have distal finger involvement, you need a variety of other criteria to make that diagnosis. You can get points for having interstitial lung disease. You can get points for having pulmonary hypertension, Raynaud's phenomenon, digital pits or digital ulcers, or even just puffy fingers, telangiectasias.

You can also get points for the characteristic rheumatologic antibodies that go with scleroderma, such as the Scl‑70 antibody or the anticentromere antibody, or one called RNA polymerase III. All those are weighted differently. They are assigned a different number of points. You add them up together and if you have 9, that's a definite diagnosis of scleroderma. If you have 8 points, that doesn't mean you don't have scleroderma. It means that for our research purpose, you don't meet the strict criteria. ‘

Certainly, when we see those scleroderma‑specific antibodies, like the Scl‑70, or the RNA polymerase III, or the anticentromere antibody, we start watching that patient pretty carefully to see what's going to evolve.

RM: You mentioned interstitial lung disease. Of course, this is a very serious complication. Do you have a sense of what percentage of patients with scleroderma go on to develop ILD, and are there certain patients that are at greater risk?

Dr Highland: That's a good question. It depends on how you're looking for interstitial lung disease.

If you do HRCT, high‑resolution chest CT scan, you can probably see at least a little bit of interstitial lung disease in over 80% of patients. Fortunately, clinically significant interstitial lung disease is 40% or less than that. We worry about interstitial lung disease. It's something that happens early in the disease course.

The minute you get your diagnosis of scleroderma, we recommend getting a HRCT as well as pulmonary function test, breathing test to screen for interstitial lung disease. Even with normal pulmonary function testing, the HRCT can have some early abnormalities.

It's with the new diagnosis of scleroderma is when we see the greatest decline in lung function if it's going to happen. We want to be looking for interstitial lung disease and following patients very carefully along those lines really early.

The farther away you get from your diagnosis, the less you have to worry about the interstitial lung disease, but then you start worrying about the pulmonary hypertension, which tends to occur later in the disease course.

There are risk factors for progressive interstitial lung disease. Any form of scleroderma can get ILD, but we think about it a little bit more in the diffuse cutaneous variant. We think about it more in patients who have that Scl‑70 or antitopoisomerase I antibody. Those are a little bit more frequent in early disease. Those who also have primary cardiac dysfunction.

We worry about severe interstitial lung disease in African Americans in particular, and especially in male African Americans. They can have the worst prognosis as far as interstitial lung disease goes.

RM: Are there signs and symptoms that a rheumatologist can pay attention to, that they might notice that would be an indication that this is starting?

Dr Highland: Sometimes, that's hard to tease that out with patients with an underlying rheumatologic disease, because the first symptom is shortness of breath or dyspnea with exertion.

Sometimes, these patients are not moving around a lot, because they feel bad because of their disease. They're not moving around so much, so they might not know that they're short of breath.

If you press your patient, "Can you go to the grocery store? Can you carry your groceries in? Can you go up a flight of stairs?" sometimes, they'll be able to tell you, "Yeah, I don't do as well as I did five years ago."

A nonproductive cough is very, very common. Patients may complain of that or may endorse it if you had asked it. On exam, you can hear crackles with your stethoscope on examination. The presence of crackles should definitely be a clue that there's probably some interstitial lung disease.

RM: When you find interstitial lung disease, what can you do about it?

Dr Highland: We think about the 3 pathways that are at play, which is the fibrotic pathway, the inflammatory pathway, and the vascular pathway. In regards to interstitial lung disease, we have therapies that target that fibrotic pathway and therapies that are immunomodulators.

Our first little bit of hope that we could do something to improve or at least slow the rate of decline in pulmonary function was with cyclophosphamide, which is a type of chemotherapy. It's something that has cumulative side effects. It's something that you can't take forever without paying the consequences.

Then mycophenolate was compared to cyclophosphamide. That was Scleroderma Lung Study II. Mycophenolate is something that people can take long term. It's used in the transplant world. That study showed that just like cyclophosphamide, there's a modest improvement in pulmonary function testing in people that got that, so it's a viable alternative.

Staying on the immunomodulator side, there was recently a study, it was a skin study for people with very early scleroderma, very inflamed phenotypes. Their inflammatory markers were up. The drug tocilizumab was tried.

It was a negative study in regards to the skin, but they looked at the lungs as a secondary endpoint. First of all, what they found is despite having normal function, 65% of the patients had evidence of interstitial lung disease on CT scan. They were finding interstitial lung disease early.

The patients that were randomized to tocilizumab versus the patients randomized to placebo that had that evidence of interstitial lung disease, almost 25% of the placebo group had a decline in their forced vital capacity by 10% at 48 weeks, which is a substantial difference, a clinically significant difference, whereas, it was only 8% in the tocilizumab group.

Then, they looked at quantitative fibrosis scores by CT scan. It showed some improvement in fibrosis in people getting tocilizumab.

With that data, tocilizumab is now FDA‑approved for scleroderma‑associated interstitial lung disease, recognizing that it was studied in a very specific scleroderma patient population.

If you move over to the fibrotic side, there are two antifibrotics that are FDA‑approved for idiopathic pulmonary fibrosis, that have both been looked at in scleroderma.

Pirfenidone is the agent that's being looked at in Scleroderma Lung Study III, a phase 3 study, which is finishing up. Those patients are being randomized to upfront combination therapy, so mycophenolate plus pirfenidone versus mycophenolate plus placebo. Hopefully, we'll have some data on that soon.

The other study called the SENSCIS study randomized patients to nintedanib versus placebo. Patients were able to be on background mycophenolate or methotrexate, but they had to be on stable dose for 6 months.

In that study, nintedanib slowed the rate of forced vital capacity decline compared to placebo, with I think it's a 44% risk reduction. That's definitely clinically and statistically significant.

That was a very large study. The largest scleroderma ILD study to date, 580 patients, half of whom were on background mycophenolate and half of whom, like many in other countries that don't have availability of mycophenolate, were just on nintedanib monotherapy.

Based on those data, nintedanib got FDA‑approved for scleroderma‑associated interstitial lung disease. The study wasn't designed to determine, is combination better than monotherapy? If you look at the subgroup analysis, combination therapy seems to be numerically better than either monotherapy.

There will likely be a movement where we're targeting both pathways. We're trying to sort all that out still, but that's what's happening.

Interviewer: Do you have any additional thoughts or advice you'd like to share with rheumatologists about diagnosing and caring for patients with scleroderma and those with associated interstitial lung disease?

Dr Highland: I would say screen, screen, screen. That's number 1. Get that first CT scan, get those PFTs. Particularly if your patient has newly‑diagnosed scleroderma, get repeat pulmonary function testing every 3 to 6months for the first 3 to 5 years of their disease.

If nothing's happening, you can space it out to yearly. In that initial stage, look, look, look for the interstitial lung disease, because we now have therapies.

Fibrosis is not reversible, so if we can prevent it, if we can intervene before we have that downhill slide, we can preserve exercise tolerance and functional ability and independence and quality of life for our scleroderma patients.

I feel like it's a new era in scleroderma. There's a lot of hope. There's a lot of activity that's happening. I'm excited to be part of it.