When skin turns to stone

"I have systemic sclerosis. It's an auto-immune disease that causes my immune system to attack my body’s own tissue. My skin has become hard and rigid in lots of places, mainly on my hands. When exposed to cold, my fingers quickly turn white or blue – this is called Raynaud’s. I'm often tired, and sometimes my lungs cause problems with my breathing." This is how someone suffering with systemic sclerosis would describe their disease. Systemic sclerosis (SSc) is a rare auto-immune disease, yet it is also one of the most dangerous of the rheumatological diseases. Its symptoms range from circulatory disorders, hardened skin and inflammation, to severe lung damage and organ failure. The disease is often diagnosed late. There is currently no treatment that completely halts the disease.

A race against time

At University Hospital Zurich, rheumatologist and professor at the University of Zurich Oliver Distler is working on changing that. Together with an interdisciplinary team, he is researching the preliminary stages of the disease and developing methods intended to predict the risk, progression and treatment options on a patient-by-patient basis. At the heart of his work is the project "PREVENT-SSc", which is led by Distler and supported by the translational research centre The LOOP Zurich. The project follows a precision medicine approach – and is divided into two key phases:

1. Prediction: How can systemic sclerosis be detected at an early stage, even in its preliminary stages? What does the progression of the disease look like in each case?
2. Molecular analysis and prevention: Which biological signals are in play during these preliminary stages? And how can these signals be specifically influenced before the disease progresses further and causes irreversible damage?

The disease before the disease

A key moment in the research was the finding that the early form of systemic sclerosis has a considerably different molecular makeup than the advanced form. Distler describes it as follows: "When the lungs are affected, it’s already too late for many treatments. Therefore, we need to focus on the preliminary stage – where the course is set." Certain early signs can already be determined as things stand. These include:

• Raynaud's phenomenon: Fingers turn pale or blue when exposed to cold.
• Autoantibodies: Certain antibodies in the blood indicate an auto-immune response.
• Capillaroscopy: Changes in the smallest blood vessels can be made visible.

Using these markers, the Zurich research team can predict with a high degree of certainty whether a person will develop systemic sclerosis within the next few years. The basis for this is data collected by Distler from a cohort of over 200 patients in the early stage. "We need studies that specifically concentrate on the early forms", explains Distler. "This is what we're looking at now."

High-omics methods against sclerosis

Notwithstanding the above, prediction alone is not sufficient. The second part of the project concentrates on identifying key molecular factors that influence the progression of the disease and which may be useful for treatments. This involves the use of so-called high-omics methods: the latest technologies from the fields of genetics, protein research and cell biology. These technologies include:

• Single-cell sequencing: A method used to investigate the genetic activity of individual cells.
• Proteomics: The large-scale study of proteins that change as a disease progresses.
• Biomechanical skin analysis: This involves using devices developed in-house to measure skin elasticity, a possible indicator of the early fibrosis process.

Distler has put together a team of researchers who each work on different areas. For example, a team at ETH Zurich is investigating the mechanical properties of skin. Another research is measuring the LOX enzyme, which plays a role in the formation of connective tissue. At the same time, bioinformatics researchers are developing prediction models based on hundreds of clinical and biological parameters – with the help of artificial intelligence and machine learning.

From prediction to prevention

The "PREVENT-SSc" project is initially scheduled to run for three years. The objective is to produce a reliable prediction model which creates individual risk profiles and indicates if and when preventative treatment may be sensible. But the work doesn't end there. As part of the next steps, the plan is to develop and test concrete therapeutic interventions – such as medications that as of now are only used in cases where the disease is advanced. One such medication is Nintedanib, whose development Distler himself was involved in. It can slow down lung fibrosis, but currently only in the late stage.

International reputation

The Department of Rheumatology at University Hospital Zurich has established itself as one of the world’s leading centres in the last few years. Oliver Distler's department is one of the best research institutions in the world in the field of systemic sclerosis – measured in terms of publications, international cooperation and innovation. Junior researchers from all over the world come here to take in all the expertise Zurich has to offer. And perhaps to achieve what has long appeared impossible: to stop system sclerosis in its tracks – even before it takes hold.

Systemic sclerosis

Consultation at the University Hospital Zurich

Text: Marita Fuchs
Pictures: Frank Brüderli
Video: Frank Brüderli
University Hospital Zurich: Oliver Distler, Dobrota Rucsandra
University of Zurich: Christian Stockmann
ETH Zurich: Helma Wennemers, Sabine Werner, Edoardo Mazza
University of Fribourg: Jörn Dengjel