June 11, 2024 | Sarcoidosis is difficult to diagnose for a variety of reasons, Mary McGowan, CEO of the Foundation for Sarcoidosis Research, told Diagnostics World. For one, it is not limited to a single area or part of the body. “It’s a rare inflammatory disease that can impact literally any organ,” she said.
Although the vast majority of people living with sarcoidosis have it in their lungs, it can also appear in the eyes, the skin, brain, heart, spinal cord, liver, kidney, and even in the bones. “So it’s challenging from that perspective, because it impacts so many different organs,” she added.
The disease causes the immune system to form clusters of cells known as granulomas. And while it resolves on its own for some, sarcoidosis can be a lifelong condition for others. In serious cases, it can lead to issues like fibrosis, blindness, or heart failure. And for the time being, the exact underlying cause of this disease remains unknown.
Sarcoidosis is a heterogeneous disease that is often referred to as a “snowflake disease” because no two patients have the same symptoms or disease progression, McGowan pointed out, “so that's another challenge.” Furthermore, it is known to be “a great mimicker” because it can resemble plenty of other health issues, such as tuberculosis, lupus, lung cancer, or multiple sclerosis. “So there’s a lot of misdiagnoses.”
It is often treated as a disease of exclusion, she added, meaning a number of other conditions typically need to be ruled out before someone is diagnosed with sarcoidosis. Despite these sorts of difficulties, researchers—and the funders supporting their work—are continuing to make progress toward improved diagnostic and treatment options.
Blood Test Aims to Speed Along Diagnostic Process
When it comes to recent developments in this space, McGowan said one of the most talked about efforts comes from Lobelia Samavati at Wayne State University, who is a previous recipient of a research grant from the Foundation for Sarcoidosis Research.
She and colleagues developed a new project supported by the National Institutes of Health (NIH) that has led to the development of a tool meant to quickly and inexpensively diagnose sarcoidosis. The underlying idea is that a simple blood test could help reduce the use of more invasive tests that are relied upon to identify this disease.
“Dr. Samavati believes that they may have developed a blood test that would be able to show immunoglobulin antigens that could indicate sarcoidosis,” McGowan said. The research group “may have identified two newly-described disease specific antigen biomarkers that only bind to the antibodies of sarcoidosis positive patients.”
The current process of diagnosing sarcoidosis involves the removal of tissue and testing with additional screenings that are meant to rule out other potential diseases, according to James Kiley, director of NIH’s Division of Lung Diseases at the National Heart, Lung, and Blood Institute. “Using a blood test will help diagnose faster, particularly in those organs that are more challenging to biopsy and with less harm to the patient,” he said.
The specific antigens that cause inflammation in sarcoidosis are not yet known, according to Samavati and colleagues at Wayne State University, and there is no specific test to diagnose this disease. To pinpoint specific antigens that could be associated with sarcoidosis, they gathered blood cells and lung fluid samples from patients with pulmonary sarcoidosis and extracted genetic material. Using molecular techniques, they zeroed in on two biomarkers in particular: Cofilinμ and Chain A.
From there, the researchers developed a blood test to see if they could accurately detect the disease. To verify their test, the group compared samples from nearly 400 people, including patients with sarcoidosis, tuberculosis, lung cancer, and healthy individuals. They found that their approach can differentiate between people with sarcoidosis and those with different types of respiratory diseases.
Findings published in the American Journal of Respiratory and Critical Care Medicine (DOI: 10.1164/rccm.202306-1054OC) revealed that the researchers’ Cofilinμ model resulted in a mean sensitivity of 0.97, specificity of 0.9, positive predictive value (PPV) of 0.9, and negative predictive value (NPV) of 0.96. The same measures for the Chain A IgG antibody were 0.9, 0.83, 0.84 and 0.9. Combining both of the biomarkers, meanwhile, led to improved area under the curve, sensitivity, specificity, PPV, and NPV. “These results provide a novel immunoassay for sarcoidosis,” the study authors concluded.
Although additional work is needed before this screening method would be ready for use within clinical settings, Samavati indicated this could become a reality in the years ahead. “Because we extensively validated our discovery in our lab, it may be sooner,” she told Diagnostics World. Their finding needs to be re-validated by a third party to allow for FDA approval through the laboratory-developed tests (LDTs) pathway.
Samavati indicated that her team has been in discussion with several companies that have expressed interest in pursuing the development of a test kit. She also highlighted the encouragement received from clinicians, patients, and investigators worldwide. “This support encourages me to move forward to bring this test to the sarcoidosis community,” she said.
From her vantage point, though, the most exciting aspect of this line of work is not the potential for a test but rather the discovery of potential antigens in sarcoidosis because (once confirmed) this could help facilitate the development of a model and the identification of the molecular mechanism involved. “Once that is developed, then we can identify the treatment,” she added.
In Pursuit of New Treatment Options
There are a number of other research groups that are working toward improved treatment options for sarcoidosis. In a small clinical study, a group from Medical University of Vienna and the Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM) found that the inhibition of the mTOR (mechanistic target of rapamycin) pathway, which regulates metabolism and growth in various cell types, showed promise in the treatment of granulomas in the skin.
The single-center, randomized study included 16 patients with granulomas of the skin and other organs. The researchers used sirolimus, an mTOR inhibitor that was initially approved many years ago to help prevent organ rejection following kidney transplants. First, sirolimus was delivered to the participants as a cream and then as an oral solution. Although the topical treatment was unsuccessful, the researchers found that systemic treatment helped 7 out of 10 patients.
The participants who responded to systemic treatment had higher mTOR expression in their granuloma fibroblasts than the participants who did not respond well to this form of treatment. “We suspect that, unlike broad-spectrum immunosuppressants, mTOR inhibition targets both immune and non-immune cells in granulomas, which prevents a recurrence of tissue granulomas,” said study lead Georg Stary.
The research findings were published in the journal Lancet Rheumatology (DOI: 10.1016/S2665-9913(23)00302-8). “Short-term treatment with systemic sirolimus might be an effective and safe treatment option for patients with persistent glucocorticoid-refractory sarcoidosis with a long-lasting disease-modulating effect,” Stary and colleagues wrote.
The study suggests that systemic treatment impacts granulomas in other organs, too, and the researchers are planning a multi-center clinical trial with a larger number of participants to confirm their initial results and to learn more about the treatment’s impact on the lungs, considering this organ is involved in most cases of sarcoidosis.
“Given the rarity of sarcoidosis and the fact that mTOR inhibitors such as sirolimus are no longer patented, research interest from the industry is limited,” Stary noted. Because of this dynamic, he highlighted “the importance of investigator-initiated studies and academic research” in this field.
Meanwhile, researchers at Kyoto University in Japan have discovered a metabolic pathway specific to granuloma formation in sarcoidosis patients, and according to lead researcher Kenji Kabashima, their findings suggest that metabolic enzymes could have potential diagnostic and therapeutic applications.
“Currently, the only approved treatment for sarcoidosis is glucocorticoid-based therapy,” they wrote in a Journal of Clinical Investigation paper (DOI: 10.1038/s41597-023-02468-6). This treatment is not ideal, they pointed out, considering it involves long-term administration and can lead to serious side effects like hyperglycemia or osteoporosis.
TNF-α inhibitors have been studied, too, although efficacy differs from person to person and some studies have found no benefit, they continued. Furthermore, Janus kinase inhibitors that are in clinical trials “have been reported to improve symptoms,” but could heighten the risk of carcinogenesis and infection. For these reasons, the researchers believe there is an urgent need for new and improved therapeutic options.
In their study, they found that macrophages produced granulomas via a hyperactive pathway known as the pentose phosphate pathway (PPP). Single-cell RNA sequencing enabled the research group to find signs of the macrophages both in the skin of sarcoidosis patients and in lesions located throughout the body.
The inhibition of PPPs, and especially FBP1, could be a new target with potential to limit the side effects involved. Using PPP inhibitors consistently reduced granuloma formation both in vitro and in a mouse model, revealing potential therapeutic efficacy, said Satoshi Nakamizo of Kyoto University Graduate School of Medicine’s Department of Dermatology.
In yet another line of work, Lynn Hassman, assistant professor of ophthalmology at the University of Colorado School of Medicine, is pursuing efforts to define ocular sarcoidosis in order to help patients, doctors, and efforts geared toward more personalized treatments.
According to Hassman, who is also a specialist in the Department of Ophthalmology’s Center for Ocular Inflammation, sarcoidosis is likely several diseases that could potentially be defined differently depending on the body part or the molecules driving the inflammation.
She is recruiting uveitis patients for a study that will analyze a sample from the eye using single-cell RNA sequencing. The goal is to learn more about the molecules that cause eye inflammation in patients and better understand the different immune response types in the eyes in hopes of eventually arriving at more personalized treatments. The research will look to group uveitis patients based upon treatable molecular features, like IL-6 or TNF-driven inflammation, rather than relying on terms like sarcoidosis.
“Even if we give a patient a diagnosis of sarcoidosis, we don't really know how to best treat it right now,” Hassman said. Improving the ability to define disease subtypes and then apply molecular techniques could ultimately help researchers “understand what’s driving the inflammation and what is targetable with drugs.”
Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com.