Cell-released proteins may predict sarcoidosis treatment response

Levels of certain proteins carried by extracellular vesicles (EVs), tiny cargo-filled sacs released by cells, may help predict whether people with pulmonary sarcoidosis respond to standard treatment with prednisone or methotrexate, a study suggests.

Higher levels of three EV-carried proteins involved in immune responses were associated with a better response to prednisone, while lower levels of another EV-carried immune protein were linked to a better response to methotrexate, potentially paving the way for more personalized treatment.

“These findings support the potential of EV [protein analysis] as a minimally invasive tool to guide personalized treatment selection and improve clinical outcomes,” the researchers wrote.

The study, “Identifying protein signatures in vesicles associated with treatment response in pulmonary sarcoidosis,” was published in Extracellular Vesicle.

Pulmonary sarcoidosis is marked by the formation of small clumps of inflammatory cells, called granulomas, in the lungs, leading to sarcoidosis symptoms including shortness of breath and cough.

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First-line treatment for sarcoidosis involves oral corticosteroids, such as prednisone, which are anti-inflammatory and immunosuppressive medications. However, their long-term use is associated with serious side effects, and a large proportion of patients don’t respond to them. Methotrexate, another immunosuppressive treatment, is commonly used when prednisone is not an option or is ineffective.

“Recent studies have shown that the effect of MTX [methotrexate] is [not] inferior to prednisone in terms of change in lung function, further increasing the unmet need for biomarkers that can guide treatment steps and predict treatment response to both prednisone and MTX in sarcoidosis,” the researchers wrote. “Early selection of the most optimal therapy could substantially improve patient outcomes by reducing non-responsiveness, limiting treatment switching and side effects, and preventing irreversible organ damage.”

Most cells release EVs to communicate with neighboring cells. These have been shown to be key for normal lung function. In a previous study, a team of researchers in the Netherlands showed that EV-carried proteins could potentially be used as biomarkers of treatment response in people with pulmonary sarcoidosis.

Now, the same team used a more comprehensive approach to identify proteins inside EVs that could predict response to prednisone or methotrexate.

They initially analyzed levels of EV-carried proteins in blood samples from 40 people with pulmonary sarcoidosis — 20 treated with prednisone and 20 with methotrexate. Before treatment, there were no significant differences in lung function between the two treatment groups.

A total of 67 EV-carried proteins were found at significantly different levels between patients who responded to prednisone and those who did not, and 38 showed significantly different levels between those who responded to methotrexate and those who didn’t.

Six of these differentially produced proteins overlapped between the two groups, suggesting that some biological processes may be associated with responses to each treatment.

The team then selected the five EV-carried proteins showing the highest significant differences between responders and non-responders in each treatment group to be validated in a larger group of pulmonary sarcoidosis patients (40 treated with prednisone and 50 with methotrexate).

Pre-existing data from these patients showed that four of these proteins remained significantly associated with treatment response.

Participants who responded to prednisone had significantly higher levels of three proteins linked to immune regulation — serpin A3, complement factor H (CFH), and complement factor I (CFI) — before treatment than those who didn’t. In the methotrexate group, responders had significantly lower levels of the complement protein C8 before treatment than non-responders. CFH, CFI, and C8 all belong to the complement cascade, a part of the immune system.

None of these differentially produced proteins showed significant differences between responders and non-responders when measured in whole blood rather than within EVs.

“This suggests that the observed associations are specific to the EV-enriched fraction rather than reflecting differences in total circulating protein concentrations,” the researchers wrote, adding that EVs “may provide a more sensitive and biologically relevant source of biomarkers.”

Among patients receiving prednisone, higher EV levels of serpin A3, CFH, and CFI were significantly associated with greater improvements in lung function after 24 weeks (about six months). This was assessed with forced vital capacity (FVC), a measure of how much air a person can forcefully exhale after a deep breath. Higher CFH levels were also significantly associated with greater improvements in the lungs’ ability to transfer oxygen into the bloodstream.

No such associations were found in the methotrexate group.

In a second validation group, comprised of 11 patients treated with prednisone and 11 with methotrexate who were followed over time, EV-carried CFI remained a significant predictor of prednisone response, while EV-carried C8 showed only a trend toward a level difference between methotrexate responders and non-responders.

In the prednisone-treated group, higher serpin A3 levels were also significantly associated with greater FVC improvements over 24 weeks.

“These findings indicate that EV protein profiles differ between responders and non-responders to prednisone or MTX in pulmonary sarcoidosis and may support future personalized treatment selection,” the team concluded.