Immune cell counts at first IgG4-RD treatment may predict future flares
Researchers note lack of 'reliable' markers to ID those at high relapse risk
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When starting treatment for IgG4-related disease (IgG4-RD), having measurements of certain immune cell levels may help doctors predict the risk of future disease flares in those with the rare condition, a new study from Japan suggests.
The researchers found that high blood levels of two types of immune cells — CD19-positive B-cells and Tph2 cells — were independent predictors of disease relapse in individuals with IgG4-RD, in which immune cells mistakenly accumulate in virtually any organ of the body.
The team noted that “relapse is common in IgG4-related disease … but reliable predictors to identify high-risk patients remain limited.” Given this, the scientists had been looking for identifying features, assessed when trying to induce disease remission, that could be linked to future flares.
“We identified a distinct immune signature at the time of remission induction therapy that [is] potentially associated with subsequent disease relapse,” the researchers wrote. “Higher baseline [initial] Tph2 cell counts and lower [CD19-positive] B cell counts in … blood are independently associated with relapse, stratifying patients into high- and low-risk groups.”
According to the team, “these findings may inform risk-adapted monitoring and treatment strategies in IgG4-RD.”
The study, “Extrafollicular Tph2-like cell dominant tissue pathotype is associated with relapse in IgG4-related disease,” was published in the journal Rheumatology.
An inflammatory disease, IgG4-RD is marked by abnormal clumps of immune cells, mostly plasma cells that produce high amounts of the IgG4 antibody, which can form in various organs and give rise to a wide range of symptoms.
Plasma cells are fully-matured B-cells, a broad class of immune cells responsible for making antibodies and helping to coordinate immune activity.
“IgG4-RD is characterized by dysregulated T–B cell interactions, with T peripheral helper (Tph) cells implicated in [disease-associated] … B cell responses and tissue inflammation,” the researchers wrote. T-cells are type of immune cell that regulates other immune cells and are able to kill other cells.
Higher, lower numbers of 2 immune cells linked to relapse
Generally, the initial treatment of IgG4-RD uses immune-suppressing drugs to drive the disease into remission, or inactivity. The goal is to allow for long-term remission, but many patients experience relapses, where the disease reactivates after initially achieving remission.
To date, there have been no reliable ways developed to predict whether an individual with IgG4-RD is at a higher or lower risk of relapse after initial remission.
Now, seeking immune markers of future remission risk, the scientists used blood samples from 74 people with active IgG4-RD who began remission induction therapy at Keio University Hospital in Tokyo. The team analyzed levels of many different types of immune cells.
The patients’ median age was 64, slightly fewer than half were female, and the most commonly affected organs were the eye socket or tear glands (70%) and salivary glands (66%). Over a median follow-up time of nearly three years, which spanned as long as 10 years, approximately 1 in 4 patients experienced a relapse — all in previously affected organs.
The researchers then constructed statistical models looking for significant associations between immune cell markers and the long-term risk of relapse.
These models showed that specific types of IgG4-RD treatment were not significantly associated with long-term relapse risk. However, two types of immune cells were significantly linked to a future relapse, albeit in different ways.
Individuals who relapsed had significantly lower numbers of CD19-positive B-cells, but higher counts of Tph2 cells, the researchers found.
CD19 is a cell membrane protein present across nearly the entire B-lineage, from early immature B-cells to mature B-cells, but absent in plasma cells, which produce high amounts of antibodies. Meanwhile, Tph2 cells are a type of T-cell marked by a cell-killing profile and thought to promote inflammation in tissues.
Findings could lead to new model for predicting flares
Further analyses showed that higher baseline Tph2 cell levels were significantly associated with higher disease activity, IgG4 levels, number of affected organs, and Tfh2 cell and plasma cell counts.
Data from available blood samples taken over time demonstrated that Tph2 cell counts dropped significantly with induction treatment, “paralleling clinical improvement,” the researchers wrote.
In addition, analyses of tear gland samples collected from 18 patients at diagnosis showed that in those who later relapsed, there was an accumulation of Tph2-like cells with relatively low B cell infiltration, called a T-B-pathotype.
These findings suggest that “higher Tph2 cells and lower [CD19-positive] B cells in blood and T-B-pathotype in [tear] glands are potentially associated with increased relapse risk in IgG4-RD,” according to the team.
The researchers speculated that Tph2 cells may promote B-cell activation and maturation into plasma cells, which would explain both the lower counts of immature CD19-positive B-cells and the link with relapse risk.
“These findings support a model in which Tph2-driven [B-cell maturation] contributes to a T cell–dominant inflammatory niche that predisposes to disease relapse in IgG4-RD,” the researchers wrote.
If that’s the case, then targeting Tph2 cells may be a useful strategy for preventing relapse in high-risk IgG4-RD patients, the researchers noted. The team called for further studies to test this idea. In addition, because the study was limited to just a few dozen patients, the findings “warrant validation in larger [studies],” the team concluded.
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