Researchers discover key to new treatment approaches for rheumatic diseases

The standard treatment for many rheumatic diseases are corticosteroids. However, patients often develop resistance or suffer from severe side effects. This prompted researchers at the Medical University of Innsbruck to work on new treatment methods that reduce inflammation in specific conditions in a more targeted manner.

Biology and Medicine

by Alois Pumhösel

October 12, 2026

What we call “rheumatism” in everyday language encompasses hundreds of different conditions. The common denominator between them is that they hamper movement and cause pain. One of these many rheumatic diseases is polymyalgia rheumatica (PMR), which is characterized by pain and stiffness primarily in the shoulder and pelvic regions. The underlying inflammatory processes usually affect the tissue surrounding the joints – unlike arthritis, which affects the interior of the joint itself. In almost all cases, the people concerned are over the age of 50, and women are two to three times more likely to be affected than men. At the same time, there is a pronounced north-south gradient, with most cases occurring in northern countries. Among the reasons medics assume to be responsible are genetic factors, UV radiation, and vitamin D levels. PMR often occurs simultaneously with the closely related giant cell arteritis (GCA), an inflammation of the blood vessels. If the arteries of the eyes are affected, this constitutes a medical emergency that can lead to permanent blindness.

The exact causes of PMR and GCA remain unclear to this day. Also, there is no specific biomarker for diagnosing PMR – it can only be diagnosed by ruling out other conditions, such as rheumatoid arthritis. The standard treatment for both diseases is corticosteroids such as cortisone. While the medications help most, albeit not all, patients, they can cause long-term side effects such as osteoporosis, diabetes, and high blood pressure. Some patients also develop resistance to the substance. These shortcomings are reason enough to conduct further research. In the FWF-funded project “Novel anti-inflammatory intervention in PMR and GCA,” Sandra Santos-Sierra and her team at the Medical University of Innsbruck are doing precisely that.

The project is investigating what triggers inflammation in certain rheumatic diseases and how it can be specifically inhibited. In addition, the researchers are searching for biomarkers in the blood that would enable a faster and more accurate diagnosis.

Understanding and inhibiting the disease mechanism

Their research focuses on so-called Toll-like receptors, or TLRs for short. These proteins, of which ten different types (TLR1–10) are currently known in humans, are part of the innate immune system, and they recognize specific molecular patterns that suggest disease or tissue damage. “The assumption is that in GCA, cells of the innate immune system colonize the arteries first and trigger inflammation there. That’s why we wanted to examine which TLRs are involved on a large scale. It is our hypothesis that this could help us identify the trigger of the inflammation. In addition, the goal was to test TLR inhibitors – in other words substances that block the signaling cascade and prevent inflammation right from the start,” says Santos-Sierra, outlining the research approach. In a previous project, the research group had already developed several inhibitors for TLR2 that could be tested for this purpose.

For these studies, the researchers worked with tissue samples obtained through biopsies from patients with GCA and PMR and they also tested the patients’ blood plasma for inflammatory markers. They were able to use samples from the Hospital de la Princesa in Madrid and the University Hospital of Innsbruck, with which Santos-Sierra and her team collaborate on their research. The method enabling the team to detect the presence of TLRs in tissue samples is known as immunofluorescence microscopy. This involves applying antibodies to wafer-thin tissue sections, where they specifically bind to the target TLR types. Additional antibodies, which carry a fluorescent dye, subsequently bind to these. Under the microscope, the frequency and distribution of the TLRs is then revealed by the fluorescent labeling.

Unexpected immune response

The study yielded a surprising result that does not exactly make further research any easier: “Contrary to our expectations, several TLRs were upregulated in the arteries, which is why we were unable to identify a direct, specific trigger – such as viruses or bacteria – for the onset of the disease. Other inflammatory signals, known as alarmins, were also elevated. This indicates a generally heightened response of the innate immune system,” explains Santos-Sierra. Hence, these findings do not yet enable the researchers to pinpoint the triggers of the disease. The question as to whether PMR and GCA are more closely linked to a genetic mutation or a previous viral or bacterial infection cannot be answered at this point.

In a next step, the researchers investigated how the inhibition of TLRs and alarmins affects the course of inflammation. “We were able to use some very advanced inhibitors. In addition to our own development, these included TLR inhibitors that are already being studied in a clinical trial for autoimmune and inflammatory diseases such as lupus and that have not yet been tested for PMR or GCA,” notes Santos-Sierra. “In fact, it turned out that these agents can reduce inflammation.” However, for future use as a therapeutic agent, a balance must be struck between the desired anti-inflammatory effect and the risk of excessive immunosuppression.

Biomarkers could improve diagnosis

The researchers also analyzed another aspect in the blood samples. Using high-precision mass spectrometry – which identifies molecules based on their mass-to-charge ratio – they compared the plasma of PMR and GCA patients. Again, the result was surprising: “Until now, it was assumed that the two diseases were closely linked. However, we have found that the disease-associated proteins indicate significant differences between PMR and GCA.” Of a total of 146 altered protein signatures, the two diseases share only 9 percent, the researchers note in their study. Some of the proteins point to signaling pathways that have not yet been associated with PMR or GCA – and which need to be investigated for their therapeutic relevance. And there is one more conceivable clinical application: “Some of the proteins could potentially serve as biomarkers for a more accurate diagnosis,” says Santos-Sierra.

A major obstacle in the study of rheumatic diseases resides in the fact that animal models do not always replicate the clinical picture. Nevertheless, an in vivo study will be the focus of a follow-up project. Santos-Sierra also emphasizes that she intends to investigate why some patients develop resistance to treatment with corticosteroids. “The project, which is now coming to a close, has raised many new research questions. In the coming years, we will try to answer as many of them as possible.”

About the researcher

Sandra Santos-Sierra is the head of a research group at the Institute of Pharmacology at the Medical University of Innsbruck. She studied chemistry at Complutense University and earned her Ph.D. in molecular microbiology at the CIB (Centro de Investigaciones Biológicas) in Madrid. In 2009, she joined the Medical University of Innsbruck, where she earned her venia docendi in pharmacology and toxicology in 2018. Besides rheumatic diseases, Santos-Sierra’s research focuses on the role of TLRs and innate immunity in neuronal cells. Set to run from 2022 to 2026, the project “Novel anti-inflammatory intervention in PMR and GCA,” received funding from the Austrian Science Fund (FWF).