At a prize-winning poster presented at the European Committee for Treatment and Research in Multiple Sclerosis ECTRIMS meeting, held in Amsterdam, the Netherlands, from 26-28 October, 2022, data from a large series of patients with neuromyelitis optica spectrum disorders (NMOSD; previously known as Devic disease or neuromyelitis optica) indicated that seroconversion of  aquaporin-4  (AQP4)-IgG status is rare.


 

NMOSD is  characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting optic nerves and the spinal cord. For a study, serum from patients with NMOSD was tested serially to determine the true contribution of seroconversion.

A total of 163,296 patients had their serum tested for AQP4-IgG at the Mayo Clinic neuroimmunology laboratory; 5,606 were positive for AQP4-IgG and 986 with two or more tests had a positive result at any time point, 86% were female, and the median age was 46.

The proportion of patients with at least two test results whose first test was AQP4-IgG-positive and then seroreverted from a positive to a negative status was 11% (n=933 participants). Therefore, 89% remained AQP4-IgG positive. Of those who seroreverted for at least one test, 50% turned out to be transient results, with later seroconversion in subsequent tests. Seroreversion was associated with young age and low titers

In those whose tests were initially AQP4-IgG negative, seroconversion to AQP4-IgG positive status occurred in less than 1%.  Patients with sero-reversion had ongoing attacks and seroconversion is associated with subsequent low titers.  Physician’s Weekly spoke with first author and poster presenter Dr. Amy Kunchok, Assistant Professor of Neurology from the Cleveland Clinic, OH, to understand these findings better.

PW: Take-home messages?

Dr. Kunchok: “The main question that we were trying to evaluate here was: what happens over time? What’s the temporal evolution of serology in AQP4-IgG, and what sort of factors affect change in AQP4-IgG status? To that end, we used patients from the Mayo Clinic neuro-immunology laboratory data, which is a large throughput laboratory, to identify patients who were tested for AQP4-IgG from 2007 to 2021. We looked for a cohort that had at least 2 tests to determine, longitudinally, what had happened with their results. We then stratified those patients into those whose first test was positive or those that were subsequently positive and/or negative.

There were 933 patients who had the first AQP4-IgG test scored as positive and who also had at least 1 other test later. When we looked at that group, we saw that of those 830 remained positive in subsequent tests; 89% remained positive over time. The remaining 11% or to be specific, 103 participants, seroreverted. The median time of follow-up was 1-2 years. Of those 830 patients who remained positive, we looked at their titers and saw that the titers essentially stayed stable.

We then looked at that 103 who seroreverted, and we looked at a few different features. Of the subgroup of patients in that cohort that then went on to have additional tests, 50% of them actually returned to positive, showing that the seroreversion was transient. That made us consider whether the observation of seroreversion is truly reliable. We hypothesized that there might be some factors that are just causing transient seroreversions. We believe that the reversion rate actually may be much less than 11%. Analyzing independent factors excluded gender, but did point to young age (patients under 20 years) and individuals with baseline low titers were more likely to be in this cohort.  Collectively, the seroconversion being transient in individuals with already low titers suggests to us that there is perhaps a limitation with the titers just dropping below the threshold of detection and then recovering to somewhat higher titers later. These data point to the true seroconverted individuals as being probably only a fraction of the total population.”

PW: Clinical implications?

Dr. Kunchok: “In addition, when we looked at the patients for whom we had clinical and treatment data, 25% of those had ongoing attacks. This is really important because it could have implications for clinical trials. These data tell us that if you are trying to use seroconversion as an outcome measure it is not a very reliable measure of clinical activity, especially in those of younger age or with low titers. These data tell us a lot about the test overall and its reliability and that perhaps we are choosing somewhat arbitrary thresholds that may not be relevant clinically and may not predict disease activity. However, it is a fairly reliable test and people do remain at the same titers over time.

Our final conclusions were that AQP4-IgG seroreversion, as well as seroconversion, are both uncommon. Seroreversion is associated with young age and low titers and can be transient, yet it does not really reflect clinical activity. On the other hand, AQP4-IgG  seroconversion is very rare and is associated with low titers. Despite the test’s overall reliability, we suggest avoiding these measures as a surrogate for disease activity outcomes in clinical trials.”