Novel Blood Test May Improve Monitoring of aHUS Activity and Relapse, Study Shows

A novel blood test may help monitor disease activity in patients with atypical hemolytic uremic syndrome (aHUS), as well as those at risk for relapse, a preliminary study reports.

The test measures the ability of a person’s serum to activate complement factor C5b-9, which is usually higher in aHUS patients. It was able to track the normalization of complement activation in patients undergoing Soliris treatment and in those in remission. It also managed to spot all patients in the study who had a relapse, either earlier than or during a flare.

The study, “An Ex Vivo Test of Complement Activation on Endothelium for Individualized Eculizumab Therapy in Hemolytic Uremic Syndrome,” was published in the American Journal of Kidney Diseases.

aHUS is characterized by the uncontrolled activation of the alternative complement pathway, part of the immune system’s natural defense to destroy harmful bacteria or viruses, or to get rid of damaged cells.

This type of HUS is mainly associated with mutations or self-reacting antibodies (autoantibodies) that cripple the functioning of complement activation.

In search of biomarkers for aHUS-associated complement activation, a group of scientists created a new test for detecting the disease and its activity.

The novel test requires a blood (serum) sample from the patient. It relies on the ability of aHUS serum to activate and trigger the formation of C5b-9 complement factor deposits, on top of human endothelial cells (HMEC-1) in the lab.

HMEC-1 is a lab-adapted line of cells that cover the interior of blood vessels.

The study’s goal was to evaluate the test’s usefulness for detecting primary and secondary aHUS, which occurs secondary to a different disorder, and for distinguishing active disease from disease in remission.

Researchers were also interested in seeing if the test could address patients’ response to treatment with Alexion‘s Soliris (eculizumab).

A concern with Soliris treatment is whether it should be taken lifelong. “One main limitation for eculizumab (Soliris) tapering and treatment discontinuation is the absence of reliable predictors of early relapse,” the researchers stated.

Thus, two other important aims of the study were to investigate if the novel test would be a good tool for monitoring Soliris’ effectiveness and identify relapses during the tapering-off period and discontinuation of the medication.

The method was tested in serum samples of 121 patients with primary aHUS and 28 with secondary aHUS. Samples were collected during acute episodes, following remission, and during Soliris treatment.

The results demonstrated that all untreated patients tested positive for elevated levels of C5b-9 activation, regardless of disease activity, in those going through an acute episode and those whose disease was in remission without treatment for more than six months.

The assay could also identify active disease. Using non-activated HMEC-1 cells, the test was able to spot only those patients with active aHUS. Similar findings were observed for patients with secondary aHUS.

This method also indicated that Soliris therapy helped normalize complement activation of patients. Twenty patients were tested during an acute episode (before treatment) and during Soliris induction or maintenance therapy.

While on the therapy, all patients had normal or lower-than-normal C5b-9 deposits, consistent with a reduction in disease activity. 

In terms of dosage tapering, the vast majority (96%) tested normal in those taking the medicine every three or four weeks.

Notably, the test identified all those who had a relapse (five out of 22) during tapering or discontinuation of the treatment. In these patients, the increased activation of C5b-9 was associated with or preceded the clinical signs of relapse.

On the other hand, the test indicated normal levels of C5b-9 for most of those in stable remission (16 out of 17). 

These data suggest the test was able to effectively distinguish active from inactive disease and to indicate the surge of a relapse.

“A predictive biomarker would be a valuable safeguard for dosage tapering/treatment discontinuation because it would lead to early re-initiation of eculizumab (Soliris) treatment before full-blown aHUS and/or to maintain treatment in patients at risk for relapse,” the researchers wrote.

Although this test can only be done in specialized laboratories, it “may represent an advance in our ability to monitor aHUS activity and individualize therapy,” the researchers said.

They believe the test will be reproduced soon in other specialized laboratories so that clinicians will have the opportunity to use it for diagnosis and monitoring.

However, more studies are need before this test can be recommended for clinical practice. One of the issues that needs to be addressed is if the assay can efficiently predict relapses during Soliris tapering or withdrawal. Researchers are now leading an ongoing study to address this.