CD27: A Biomarker for Progression to MS?

January 25, 2017

Levels of CD27 in the cerebral spinal fluid (CSF) could be used as a potential clinical biomarker to help in treatment decisions after a first demyelinating attack to help gauge which patients will go on to develop multiple sclerosis (MS) and how aggressive their disease may be, a new study suggests.

Senior author, Rogier Q. Hintzen, MD, Erasmus Medical Centre, Rotterdam, the Netherlands, explained to Medscape Medical News that a marker has long been sought to predict which patients with a first demyelinating event, called clinically isolated syndrome (CIS), will develop MS so treatment can be started and also to identify which patients with MS will have an aggressive disease course and need more potent disease-modifying therapy.

"So far we haven't found a suitable biomarker for this purpose which is stable and for which a reliable laboratory test can be developed," he said. "We thought we would investigate CD27 as a possible biomarker as it is known to be a T cell receptor and T cells are believed to play a key role in multiple sclerosis. We also know it is detectable in cerebral spinal fluid, and is a very stable protein giving reproducible results in assays."

In the current study, the researchers show that patients with CIS who had higher levels of CD27 in their CSF were more likely to develop MS, and of those who developed MS, a higher CD27 level was associated with more active disease.

"This is only a preliminary study," Dr Hintzen commented. "It would need to be confirmed in other patient groups and with longer follow up. But if our results can be replicated in a larger sample, CD27 could become a biomarker to assess MS activity and decide on how aggressively to treat the condition."

He warned, however, that patients would need to undergo a lumbar puncture for CSF samples to be taken, which is not ideal for assessing disease activity. "Of course it would be better to have a biomarker that could be measured in the blood or urine, which wouldn't require such an invasive test, but our results show that CD27 appears to be a reliable indicator of MS activity and I believe it is the most predictive test so far reported."

The study was published online in JAMA Neurology on January 3.

"Most Predictive Test"

For the study, the researchers measured levels of soluble CD27 in 77 patients with a first episode of demyelinating disease seen between 2002 and 2015. They were compared with 30 age- and sex-matched control patients who underwent a lumbar puncture within a similar time period for reasons other than neuroinflammatory diseases.

Results showed that soluble CD27 (sCD27) levels were significantly higher in patients with CIS (mean, 31.3 U/mL) than in controls (mean, 4.7 U/mL).

Levels of sCD27 were also significantly increased in the 39 patients with CIS with a future MS diagnosis (mean, 42.0 U/mL vs 23.2 U/mL for those who didn't develop MS).

In addition, patients with CIS and high levels of sCD27 had a shorter time to MS diagnosis than patients with low sCD27 levels. After adjustment for MRI findings, oligoclonal bands, and IgG index, multivariate Cox regression analyses showed that sCD27 is an independent predictive factor for time to MS diagnosis. The hazard ratio was 2.4 per 100-U/mL increase of sCD27.

The study also found that in the patients who had a second clinical attack, those with sCD27 levels above the median value had a 5.5 times higher annualized relapse rate during follow-up than those with sCD27 levels below the median.

However, sCD27 titer did not correlate with disability as measured on the Expanded Disability Status Scale (EDSS) later in the disease course. But the researchers note that only 3 patients reached an EDSS score of 4 or more, and all of these had high sCD27 levels (greater than the median).

The authors report that 21 of the 77 patients with CIS had sCD27 levels less than the maximum level of controls, and these patients had a less active disease course.

In a multivariate analysis, the association of sCD27 with future MS diagnosis remained after adjustment for known predictive factors, such as oligoclonal bands, IgG index, and MRI abnormalities.

However, in an accompanying editorial, Jeffrey M. Gelfand, MD, University of California, San Francisco, points out that high CSF sCD27 was present in the same patients who already have high-risk MRI findings and oligoclonal bands.

"While the sample size for lower-risk subgroups was too small to exclude the possibility of an effect, high CSF sCD27 did not occur in any of the 4 patients with no subclinical MRI lesions and negative oligoclonal bands and was not significant in predicting MS conversion risk in the 10 patients with a normal MRI and positive oligoclonal bands, he writes.

He says that studies in larger CIS cohorts may show a predictive value of sCD27 even when MRI findings or oligoclonal bands are negative, but this remains to be demonstrated. "It is also possible that sCD27 may prove to be most useful as a predictor of more aggressive relapse activity generally rather than just conversion of CIS to MS," he adds.

"For now, MRI and oligoclonal bands will remain the mainstay of risk stratification in CIS," Dr Gelfand concludes. "Further research will be needed to confirm these intriguing CSF sCD27 observations in other CIS cohorts and clarify whether this robust measure of activated intrathecal T-cell inflammation can provide added or purely complementary prognostic value."

The study was supported by the Dutch MS Research Foundation. Dr Hintzen received honoraria for serving on advisory boards for Biogen Idec, Roche, and Sanofi. He participated in trials with Biogen Idec, Merck-Serono, Roche, Genzyme, and Novartis. Disclosures for coauthors appear in the paper. Dr Gelfand consulted on a scientific advisory board for Medimmune and Genentech and receives research support to University of California, San Francisco, from Genentech, MedDay, and Quest Diagnostics.

JAMA Neurol. Published online January 3, 2017. Abstract, Editorial

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