A measure of endogenous baseline interferon levels in patient blood significantly improved the ability of Dutch researchers to predict the time to a first relapse in treatment-naïve patients with multiple sclerosis (MS), according to an Oct. 5 study in Neurology. The higher the marker of endogenous interferon, they found, the longer the time to relapse.
If confirmed in a larger trial, the test could soon serve as a much-needed blood biomarker of MS progression and possibly even treatment response, in combination with MRI and standard clinical measures, according to researchers familiar with the paper.
Laura F. van der Voort, MD, and colleagues at the VU University Medical Center in Amsterdam, the Netherlands, measured baseline blood levels of mRNA for myxovirus resistance protein A (MxA) in 116 untreated, recently diagnosed relapsing-remitting MS patients and then correlated those to clinical relapses and MRI at baseline and at follow-up. The goal of the new study was to determine whether MxA mRNA expression levels in treatment-naïve patients are associated with clinical and radiological measures of disease activity.
MxA, an anti-viral protein that determines resistance to influenza, is induced in the immune system by type I interferons, and so is considered a marker of endogenous interferon levels. The mRNA expression of MxA has been previously used as a biomarker for treatment response to recombinant interferon-beta (INF-b) in MS. MxA is upregulated in responsible to recombinant INFb; absent MxA response to recombinant INFb is associated with the development of neutralizing antibodies and the occurrence of clinical relapses.
Furthermore, the new study noted, “Mx proteins are found in the plaques of treatment naïve MS patients and are demonstrated by immuno-histochemistry in viral encephalitis, confirming their role in neuro-inflammatory processes.”
DR. ANTHONY T. REDER:“The authors are to be congratulated for demonstrating that MxA mRNA is suitable as a biomarker for trials and potentially for clinic use.”
Dr. van der Voort's group selected a cut-off for MxA levels that discriminated between clinical remission and relapse at baseline (p=0.002), and was also significantly associated with contrast-enhancing lesions on baseline MRI (p=0.045).
With a median follow-up duration of 45 months, the authors reported, “low levels of MxA mRNA were associated with the occurrence of relapses (p=0.002) and contrast-enhancing lesions (CELs) on baseline MRI (p= 0.045). In addition, high baseline MxA mRNA levels were related to a longer time to a first new relapse (HR = 0.59; 95% CI 0.35 – 1.00; p = 0.044). Adding the absence of CELs to high MxA mRNA, the predictive value increased (HR = 0.35; 95% CI 0.17 – 0.74; p = 0.006), clearly showing a cumulative value for combining both factors.”
The results of the mRNA measure of MxA levels were nearly identical to those seen in a 2002 study by Anthony T. Reder, MD, professor of neurology at the University of Chicago. Rather than studying mRNA levels of MxA, however, Dr. Reder's group measured MxA protein on Western blots in therapy-naïve patients. Both studies show highest MxA levels in healthy controls, reduced levels in stable MS, and a further decline during active MS.
“We measured proteins, the van der Voort people measured mRNA,” said Dr. Reder, who wrote a commentary accompanying the new study. “The results complement each other pretty well.”
The most important finding of the new paper, he said, is that it shows that the predictive power of MxA levels, combined with MRI, are additive.
“If you had a high MxA level at baseline in this study, you had about half the chance of having a relapse during follow-up,” Dr. Reder said. Likewise, he continued, “If you had a negative MRI at baseline, again you had about half the chance of having an attack. But put them together — a high MxA and a negative MRI at baseline — and you were down to only about one-third of a chance of having a relapse.”
“The authors are to be congratulated for demonstrating that MxA mRNA is suitable as a biomarker for trials and potentially for clinic use,” he wrote in the accompanying editorial.
Dr. Reder and other neurologists who specialize in MS agreed that a larger study should seek to determine if MxA levels could in fact be used as a biomarker of treatment response.
“It would be interesting to know if we could use this test to predict which patients will do well on interferon beta, and help us decide early which patients to give it to,” said Anne H. Cross, MD, professor of neurology and section head of neuroimmunology at Washington University School of Medicine in St. Louis. “This paper did not show that, but with larger numbers the question should be answered.”
Replication of the van der Voort findings will likely come soon from other researchers, said Jeffrey Cohen, MD, director of experimental therapeutics at the Cleveland Clinic Mellen MS Center.
“I know there are other people looking at other interferon response genes,” Dr. Cohen said. “They look at some gene expression levels before and after someone starts interferon. I think corroborative data will come out quickly.”
DR. JEFFREY COHEN said replication of the van der Voort findings will likely come soon from other researchers.
No commercial laboratory as yet offers a standard test of MxA mRNA, but developing such tests should be relatively straightforward for most research centers, Dr. Cross said.
“I think my own lab could probably set up this test without much trouble,” she said. “One of the nice things is it's on blood, not spinal fluid.”
Investigators reported that high levels of myxovirus resistance protein A seemed to predict a longer period to a relapse in patients with multiple sclerosis.