4 blood proteins may help improve IgG4-RD diagnosis and tracking
Study: Biomarkers could distinguish the disease from conditions with similar signs
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Four blood proteins may help diagnose immunoglobulin G4-related disease (IgG4-RD), monitor disease activity and treatment response, and predict relapse risk, a study reveals.
The four proteins also showed strong associations with standard markers of inflammation and could distinguish the disease from conditions with similar signs, including cancer.
“These insights advance our understanding of the molecular underpinnings of IgG4-RD and highlight promising biomarkers for improving diagnosis, monitoring, and prognostic stratification in clinical practice,” researchers wrote.
The study, “Identification of candidate biomarkers for diagnosis, disease activity, and relapse prediction in IgG4-related disease,” was published in Arthritis Research & Therapy.
There’s no universal set of criteria for diagnosing IgG4-RD
In IgG4-RD, immune plasma cells that secrete the IgG4 antibody infiltrate tissues, causing long-lasting inflammation and scarring. This results in the formation of tumor-like masses or tissue enlargement that can damage organs. IgG4-RD follows a relapsing-remitting pattern, with periods of new or worsening symptoms (relapses) alternating with periods of relative stability (remission).
“Currently, definitive diagnosis relies on a combination of clinical manifestations, elevated [blood] IgG4 levels, and [tissue-based] findings,” the researchers wrote.
However, there’s no universal set of criteria for diagnosing IgG4-RD. Although some potential biomarkers for diagnosing and monitoring IgG4-RD have been identified, none have been thoroughly tested or widely adopted in clinical practice.
“There remains a critical need for noninvasive, clinically applicable protein markers capable of accurately diagnosing IgG4-RD, evaluating disease activity, and predicting long-term outcomes,” the researchers wrote.
Levels of 4 proteins tracked course of the disease over time
With this in mind, a team of researchers in China analyzed the levels of 92 proteins in the blood of 11 people with IgG4-RD and 11 age- and sex-matched healthy individuals. They found that four proteins — PD1, OX40, CCL19, and MMP12 — were significantly elevated in IgG4-RD patients and strongly associated with established markers of inflammation.
The levels of these four proteins also tracked the course of the disease over time, dropping when patients responded to treatment and rising during relapses. They paralleled blood levels of IgG4, eosinophil counts (a type of white blood cell), and measures of disease activity.
Researchers then evaluated the diagnostic accuracy of each protein in an independent group of 140 IgG4-RD patients and 80 healthy controls using a measure called area under the curve (AUC). AUC ranges from zero to one, and the higher the AUC value, the better the classifier is at distinguishing people with a given disease from those without it.
PD1 performed best, with an AUC of 0.90. It was followed by CCL19 (AUC of 0.88), OX40 (AUC of 0.87), and MMP12 (AUC of 0.70). When the results from all four proteins were combined, the diagnostic accuracy improved further, reaching an AUC of 0.94.
Importantly, PD1, OX40, and CCL19 identified, with great accuracy, IgG4-RD patients with blood IgG4 levels below the standard diagnostic threshold, a group that’s particularly difficult to diagnose with current methods, the team noted.
All four proteins were also significantly elevated in IgG4-RD-involved salivary glands compared with normal tissues. OX40, in particular, was found in immune cell clusters known as lymphoid follicles, a characteristic tissue feature of IgG4-RD.
Higher blood levels of proteins tied to higher disease activity score
Across the entire group of IgG4-RD patients studied, higher blood levels of all four proteins were associated with higher disease activity scores, levels of markers of more severe body-wide inflammation, and a greater number of affected organs.
None of the proteins was associated with involvement of any specific organ, suggesting they are “more likely to be general biomarkers of systemic [body-wide] disease activity in IgG4-RD, rather than being specific to [disease] in any single organ,” the researchers wrote.
To examine which proteins might predict relapses, researchers followed 66 IgG4-RD patients who received standard treatment for at least one year. Of these, 20 experienced a relapse, and 46 did not. Statistical analyses showed that high PD1 levels at treatment start were an independent predictor of relapse.
We identified and validated four key proteins — PD1, OX40, CCL19, and MMP12—that not only demonstrate diagnostic utility but also exhibit strong correlations with clinical disease activity and laboratory markers of inflammation.
PD1 is an inhibitory immune checkpoint protein produced by activated immune T-cells that helps suppress self-directed immune attacks.
“Persistent high [levels] of PD1 may lead to excessive suppression of the function of immune cells, allowing persistent inflammation,” the team wrote.
Because IgG4-RD can be difficult to distinguish from other conditions, the proteins were also measured in people with three other diseases that can look similar: ANCA-associated vasculitis (AAV), pancreatic cancer, and lymphoma (a blood cancer).
All four proteins were higher in IgG4-RD patients compared with the other groups. MMP12 was notably elevated in IgG4-RD, whereas it was found at comparable levels in AAV patients, people with pancreatic cancer, and healthy controls.
“We identified and validated four key proteins — PD1, OX40, CCL19, and MMP12 — that not only demonstrate diagnostic utility but also exhibit strong correlations with clinical disease activity and laboratory markers of inflammation,” the researchers concluded. “Importantly, we established that elevated [blood PD1 levels at treatment start] serves as an independent and valuable predictor of clinical relapse.”
