AAV relapse linked to distinct gene activity signature in blood, study says
Therapies targeting neutrophil activity could potentially help prevent relapses
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Adults with ANCA-associated vasculitis (AAV) who experience a relapse after stopping maintenance therapy show a distinct gene activity signature in their blood compared with those who are newly diagnosed or in remission, a study shows.
The results point specifically to genes that control the release of pro-inflammatory molecules from activated neutrophils, a type of immune cell involved in AAV, as a feature that separates relapsing AAV from disease at its onset.
“Therapies targeting neutrophil activation could represent a novel approach for preventing or treating relapses in [AAV],” researchers wrote.
The study, “Distinct molecular signature in relapsed patients with ANCA-associated vasculitis,” was published in RMD Open by a team of researchers in Greece.
Researchers target molecular basis of relapsing disease
AAV is a group of rare autoimmune conditions in which self-reactive antibodies, called ANCAs, abnormally activate neutrophils. This triggers the release of pro-inflammatory molecules that drive inflammation and damage of small blood vessels, restricting blood flow and damaging organs, especially the kidney and lungs.
Current treatments have reduced the frequency of AAV relapses, or episodes of symptom worsening. However, they still occur in up to half of patients either during or after discontinuation of maintenance treatment, and are associated with poor outcomes.
“However, the molecular basis of relapsing disease, especially after discontinuation of maintenance therapy[,] compared with treatment-naïve, new-onset disease has not been examined so far,” the researchers wrote.
With this in mind, the team analyzed gene activity in blood samples from 21 adults (52.4% men) with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), the two most common types of AAV. A group of 12 age- and sex-matched healthy individuals served as controls.
Of the patients, 11 had active disease. Six of them had been newly diagnosed and had not yet started treatment, while the remaining five had experienced a major relapse after stopping maintenance therapy.
The remaining 10 patients were in disease remission, or periods of little to no symptoms. Four of them were on maintenance treatment with rituximab, an approved therapy for MPA and GPA, and six were off therapy.
A clear separation of relapsed patients from those in remission
When comparing active AAV patients and healthy controls, 269 genes showed significantly different activity levels in newly diagnosed patients, while this number was even higher, at 375, in relapsed patients.
In newly diagnosed patients, the genes that were significantly more active were mainly related to blood cell maturation. Gene activity increases that were exclusive to this group relative to healthy controls were linked to programmed cell death, recycling of mitochondria (the cell’s powerhouses), and TGF-beta signaling, which is linked to inflammation.
In relapsed patients, the significantly more active genes versus healthy controls were tied to certain immune system pathways and neutrophil degranulation, the process in which neutrophils release pro-inflammatory molecules.
Relapsed patients, but not newly diagnosed patients, also showed significantly increased activity of genes associated with certain pathways involved in the body’s first-line of defense, including type I interferon (IFN) signaling.
“The role of type I IFN in AAVs appears to be critical but remains to be further elucidated,” the researchers wrote.
When the two active-disease groups were compared directly, 13 genes showed significantly different activity levels, with nine of them linked to neutrophil degranulation. Still, there were no significant differences in terms of neutrophil proportions, confirming the observed differences reflect changes in neutrophil activation rather than numbers.
There was also a clear separation of relapsed patients from those in remission, regardless of therapy. Relapsed patients had significantly more activity in genes related to neutrophil degranulation and signaling of B-cells, the immune cells that produce antibodies, than those on rituximab-related remission.
These findings offer novel insights into the role of neutrophils in the [disease-associated] processes that may precede or accompany relapses in AAVs, supporting the potential to alter the disease course through targeted therapeutic approaches.
Between relapsed versus remission off-therapy groups, genes that were significantly more active in the relapsed group were related to neutrophil degranulation and mitochondrial metabolism.
Building on these findings, the researchers focused on genes linked to neutrophil-related pathways across all study participants. They found that relapsed patients showed significantly higher activity in 41 genes associated with neutrophil degranulation, clearly distinguishing them from patients at diagnosis, those in remission, and healthy controls.
Notably, a patient who displayed this pattern of elevated activity in neutrophil degranulation-related genes at the time of diagnosis showed hard-to-treat disease and subsequently experienced a major relapse while on maintenance rituximab treatment.
“Whether excessive neutrophil activation from disease onset could be associated with a subsequent [treatment-resistant] or relapsing disease course remains to be elucidated,” the researchers wrote.
The researchers concluded: “Patients with major relapses exhibited a unique [gene activity] profile, different from newly diagnosed patients, marked by a gene panel specific for neutrophil activation. These findings offer novel insights into the role of neutrophils in the [disease-associated] processes that may precede or accompany relapses in AAVs, supporting the potential to alter the disease course through targeted therapeutic approaches.”
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