Immune Checkpoint Molecules Linked to Risk of Relapse in AAV

Relapse more likely with lower sICP levels after remission and treatment

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Blood levels of molecules called soluble immune checkpoints (sICPs) may serve as biomarkers of relapse risk in people with ANCA-associated vasculitis (AAV), a study found.

Patients with lower levels of these molecules were more likely to relapse after being in remission following treatment with rituximab, but were less likely to have infections associated with the immune-suppressing treatment.

“If confirmed in another study, the panel of markers identified by our analysis might further aid in individualising treatment decisions about optimal induction therapy and the duration of maintenance therapy,” the researchers wrote.

The study, “Association of baseline soluble immune checkpoints with the risk of relapse in PR3-ANCA vasculitis following induction of remission,” was published in Annals of the Rheumatic Diseases.

AAV is caused by self-reactive antibodies, called ANCAs, that overly activate the immune system, leading to inflammation and damage to small and medium-sized blood vessels. The two main types of ANCAs are those that target the proteins proteinase 3 (PR3) and myeloperoxidase (MPO).

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Current treatments seek to push the disease into remission, a state wherein patients don’t have active symptoms, but relapses remain common. Recognizing risk factors for a relapse is important for ensuring proper treatment and follow-up. While several potential risk factors have been identified, blood biomarkers are still lacking.

Immune checkpoint molecules are involved in regulating immune T-cell activity. They exist in membrane bound or soluble forms (sICPs), with membrane-bound molecules residing on the surface of immune cells and soluble forms circulating in the bloodstream.

Membrane-bound forms have been previously linked to regulating autoimmunity, whereas less is known about the role of sICPs. Here, researchers investigated whether sICPs may serve as biomarkers of treatment-resistance or relapse risk in AAV patients.

The team analyzed blood samples collected during the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial (NCT00104299), completed in 2010, which evaluated the effectiveness of rituximab for inducing an AAV remission.

During the trial, participants received either rituximab or a standard course of cyclophosphamide followed by azathioprine (a control group), both in combination with a tapering course of corticosteroids and were monitored for remission induction and maintenance.

Blood samples collected at RAVE’s start (baseline) were evaluated for 189 out of 197 trial participants. Participants had a median age of 52 and 127 were PR3-positive; 62 were MPO-positive.

Of 14 measured sICPs, five, namely, sTim-3, sCD27, sLag-3, sPD-1, and sPD-L2, were lower in PR3-AAV patients than in MPO-AAV patients.

Remission was defined as a Birmingham Vasculitis Activity Score for Wegener Granulomatosis (BVAS/WG) of 0. A relapse was considered when BVAS/WG was greater than 0 after remission had been achieved.

Most participants achieved remission within six months except for 10 in the rituximab group and nine in the control group. Patients in the rituximab group who failed to achieve remission had lower levels of sLag-3 than those who did and also had an increase in sCD27. The same wasn’t seen among the control group.

According to researchers, this finding “must be interpreted with caution, as the number of patients in the treatment failure groups were low.”

In the rituximab trial arm, 24 out of 73 patients relapsed a median of 5.6 months after achieving remission. These 24 had lower levels of sTim-3, sCD27, and sBTLA compared with patients who achieved sustained remission. Again, sICP levels were not associated with relapse risk in the control group.

sICPs were even more strongly correlated with relapse when considered together rather than individually. While relapse rates among patients with low levels of one or none of the markers were less than 15%, relapse rates were at 50% and 84.6% among patients with low concentrations of two or three of these biomarkers, respectively.

The link between sICPs and relapse were observed specifically in patients with PR3-AAV and granulomatosis with polyangiitis (GPA), but not in those with MPO-AAV and microscopic polyangiitis (MPA), although this finding was “hampered by small sample sizes,” the researchers wrote.

Higher levels of sTim3, sCD27, and sBTLA were associated with more infections in rituximab-treated patients.

“In line with an increase immune-suppressive status (linked to response), these patients (even when only at least one of these markers was high) also suffered from higher infection rates during follow-up,” the researchers wrote.

Higher age, BVAS/WG score, newly diagnosed AAV, and prior use of steroid treatments were also each positively associated with sICP concentrations.

A longitudinal assessment of sICP concentrations was conducted for patients who also had blood samples available at six- (143 people) and 18- (87 people) month follow-ups. Results showed sICPs tended to decrease over time, but trends observed with baseline values tended to remain.

This study “highlights the potential of baseline quantification of sICP concentrations to predict [rituximab] resistance and disease recurrence in AAV,” the researchers wrote, adding follow-up research was “urgently needed to investigate the potential of sICP concentrations to predict long-term remission.”