Systemic Sclerosis: A Rare Disease That Requires Several Specialists

For unknown reasons, autoimmune diseases attack the body insidiously, often wreaking havoc and causing immense disruption to patients’ lives. There are more than 100 autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and multiple sclerosis.

Systemic sclerosis is another autoimmune disease, characterized by widespread fibrosis (replacement of normal tissue with scar tissue), vasculopathy (affecting blood vessels), and inflammation. It is a particular clinical interest of Lorinda Chung, MD, MS, professor of immunology and rheumatology and dermatology.

Systemic sclerosis is a very rare disease, less common than lupus or rheumatoid arthritis, but more common than dermatomyositis. There is a female predominance (4–5:1); however, men tend to have a worse prognosis. It typically presents in patients from their 30s to their 60s. African American patients definitely have a poorer prognosis than Caucasians, and Asians with the disease do as poorly as African Americans, as was demonstrated in Chung’s recent publication about racial disparities in systemic sclerosis based on the Kaiser Permanente Northern California database.

How Patients With Systemic Sclerosis Present

Chung describes the different manifestations of systemic sclerosis: “There are two major subtypes of systemic sclerosis: diffuse cutaneous and limited cutaneous. The subtypes are purely based on the extent of skin tightening that the patient presents with. Patients with diffuse cutaneous involvement have widespread skin tightening as well as higher likelihood of early and severe internal organ involvement, including the lungs, heart, and kidneys, as well as the muscles and joints.”

One very common feature of systemic sclerosis is Raynaud’s disease, a rare disease that reduces blood flow to the fingers and toes, causing them to turn white and become numb, which occurs in 90% of patients. Patients with the second subtype of systemic sclerosis, the limited subtype, frequently suffer from Raynaud’s and vascular phenomena like digital ulcers. These patients often live for a while without their internal organs being affected but have a higher likelihood of gastrointestinal (GI) and lung involvement later in their disease. Chung explains that “they can get severe dysmotility of their GI tract and also develop pulmonary hypertension. There are some good treatments for pulmonary hypertension, but we really struggle with treatment of the GI manifestations.”

A Special Clinic

There is a unique multidisciplinary clinic every Monday afternoon in Redwood City that focuses on the dermatologic and immunologic aspects of systemic sclerosis. Professor of dermatology David Fiorentino, MD, PhD, helped found the clinic close to 20 years ago because, as he says, “I saw a huge gap in the care of some patients if different doctors weren’t communicating in real time regarding patient care.”

Having patients seen simultaneously by both a dermatologist and a rheumatologist solved that, and the clinic is so successful, says Fiorentino, that “access is a big problem. We’re always scheduling a minimum of three to four months in advance. That is literally our biggest challenge, and it has been almost since the beginning of the clinic.”

The process that patients follow when they attend this clinic is unusual in several ways. For one thing, says Fiorentino, “we don’t see anyone in the clinic whose medical information has not been personally reviewed by either Dr. Chung or me or both. Patients carry around misdiagnoses of rheumatic diseases quite commonly, and clinic appointments are so precious that we need to make sure the appropriate patients are seen in our clinic.”

When patients arrive, they are assigned to a room where their vital signs are recorded and their medications are reconciled. They also change into a gown, which is unusual for rheumatology patients but not for dermatology patients because the skin needs to be examined. Then they are seen by a rheumatology fellow and a dermatology resident together, who go over the history, followed by targeted physical exams. The rheumatology fellow does a general medical examination with a focus on the joints and muscles. The dermatology resident assesses the skin to see how tight it is and to look for other specific skin markers of scleroderma.

After the trainees report their findings to Chung and Fiorentino and they come up with a reasonable plan, all four physicians go into the patient’s room, where, Fiorentino says, “we confirm important parts of the history with the patient, briefly examine the skin, and point out to trainees any unusual findings that might be helpful either diagnostically or prognostically. Patients often have a list of questions, as they’ve waited three or four months, and they’ve often traveled very far for the appointment.”

“At the end of the visit,” Fiorentino says, “Dr. Chung and I always bring up that we do research in the disease. We explain why it’s important to study actual patients and that complex rheumatic diseases are poorly modeled in the laboratory. We stress how rare their disease is and that this is an opportunity to turn the pain and suffering of their disease into something profoundly important and positive. When the patients better understand this perspective, 95% of them agree to be part of our research cohort and donate tissue.”

Lori Chung, MD (second from left), consults with (from left) resident Steven Mason Ronilo, MD; professor of dermatology David Fiorentino, MD; and resident Lucy Liu, MD

Internal Organ Involvement

Treatment for systemic sclerosis depends on what organ systems are involved. There’s quite a bit of data supporting the use of CellCept, an anti-rejection medication, to slow the progression of skin tightening; methotrexate can also be used. Chung uses CellCept more frequently because it helps both the skin and the lungs, whereas methotrexate doesn’t tend to help the lungs. Chung says that “clinical trials primarily target the skin, the lungs (in terms of interstitial lung disease and pulmonary hypertension), and the vascular system in terms of Raynaud’s phenomenon and digital ulcers. Most clinical trials are focused on those aspects of the disease because they’ve been best studied.”

There are many treatment choices for Raynaud’s disease, including drugs like calcium channel blockers that improve blood flow and other vasodilating therapies that are approved for pulmonary hypertension, such as sildenafil.

Chung says this is an exciting time to be involved in clinical trials for systemic sclerosis. “We now have two drugs approved for scleroderma lung disease: An antifibrotic drug called nintedanib was approved in 2019, and the anti-interleukin-6 biologic tocilizumab received FDA approval in March 2021. Stanford was involved in the clinical trials for both of these agents.”

Because of the extent of possible internal organ involvement in systemic sclerosis, Chung points out, there is a critical need for collaborations across the Department of Medicine to care for these patients. She explains their roles: “We work closely with pulmonologists for both interstitial lung disease and pulmonary hypertension in our patients. We also work closely with GI and cardiology. Because we have patients who have severe disease in their blood vessels, we work with a hand surgeon who does sympathectomies on these patients.”

“We stress how rare their disease is and that

this is an opportunity to turn the pain and

suffering of their disease into something profoundly

important and positive”

“We stress how rare their disease is and that

this is an opportunity to turn the pain and

suffering of their disease into something profoundly

important and positive”

For some patients with end-stage interstitial lung disease and/or pulmonary hypertension, lung transplant is an option. For such patients, says Chung, “we engage closely with colleagues from the division of pulmonary, allergy & critical care medicine. Because of the significant GI issues, lung transplants in patients with systemic sclerosis can be complicated by aspiration pneumonia, and therefore patients must meet certain criteria to be eligible for this procedure. Hematopoietic stem cell transplantation is reserved for patients with severe progressive systemic sclerosis. We have established a protocol in conjunction with colleagues from the blood and marrow transplantation & cellular therapy division, and in March 2021 we transplanted our second patient with systemic sclerosis.”

While systemic sclerosis is not exactly a genetic disease, there can be some predisposition. “We think there has to be some sort of trigger for the disease to actually come on,” says Chung, “and one potential trigger is cancer. We think there is immune surveillance going on in the body, where the body is trying to shut down the cancer, which is sometimes successful and sometimes not. That’s when we can see that there’s a cancer associated with the onset of systemic sclerosis or dermatomyositis.”

Chung continues, “Certain autoantibodies are associated with a higher risk of cancer in systemic sclerosis or dermatomyositis. This makes us believe that your immune cells are reacting to an antigen that is similar to a cancer antigen, and that develops antibodies in reaction to potential cancer. The autoantibody associated with cancer in systemic sclerosis is RNA polymerase III. These patients tend to have really bad skin tightening and are also at risk for developing kidney involvement, called scleroderma renal crisis. ACE inhibitors are the mainstay of treatment for scleroderma renal crisis and have greatly reduced the number of patients who have to go on dialysis.”

While systemic sclerosis is both difficult to diagnose and difficult to treat, involving such a vast assemblage of experts across the Department of Medicine improves both the access and the outcomes of patients at Stanford.