C-Reactive Protein: A Prognostic Biomarker for ALS?

Sue Hughes            

April 19, 2017

Serum levels of C-reactive protein (CRP) appear to be a "useful, feasible, and potentially prognostic factor" in patients with amyotrophic lateral sclerosis (ALS), a new study has suggested.

The authors also note that high CRP levels may identify patients with ALS who respond better to a new drug in development for the condition.

The findings were published online in JAMA Neurology on April 3, by a group led by Christian Lunetta, MD, NeuroMuscular Omnicentre, Fondazione Serena Onlus, Milan, Italy.

"CRP correlated very well with the severity of ALS in two different data sets," coauthor Stanley H. Appel, MD, chair for the Treatment and Research of ALS, Neurological Institute, Houston Methodist Hospital, Texas, commented to Medscape Medical News. "These showed that if patients are progressing faster, their CRP levels are higher. That is extremely interesting."

The researchers conclude: "Our study supports the importance of inflammation in ALS and that CRP may represent a simple biomarker obtainable from blood samples from each patient independent of his or her clinical condition."

They explain that CRP is a biomarker of the inflammatory response with a significant prognostic value for several types of tumors, cardiovascular diseases, and rheumatic diseases.

They report that a recent phase 2 clinical trial of a novel immune regulator, NP001 (Neuraltus Pharmaceuticals), a pH-adjusted intravenous formulation of purified sodium chlorite that regulates inflammation, showed no significant benefit in the overall ALS population included but suggested that patients with high CRP levels treated with the drug had a slower progression of ALS than those receiving placebo.

Noting that a previous small study has shown a significant correlation between clinical disability in ALS and some sensitive biomarkers of inflammation, including CRP, they conducted new analyses to fully examine the prognostic significance of CRP in ALS.

For the analyses they evaluated serum CRP levels at first evaluation in a large cohort of patients with early-phase ALS from an Italian tertiary multidisciplinary center and in an independent cohort from a population-based registry of patients with ALS. Finally, they performed a post hoc analysis of the phase 2 trial of NP001 to evaluate whether CRP may help identify responders to the drug.

The Italian cohort included 394 patients with ALS. Results showed that serum CRP levels correlated with severity of functional impairment, as measured by total score on the ALS Functional Rating Scale–Revised, at first evaluation (r = –0.14818; P = .004), and with patient survival.

The researchers report that "for every 1-point increase in the serum CRP level, we detected an effect of 13% on survival time" (hazard ratio, 1.129; 95% confidence interval [CI], 1.033 - 1.234).

Patients with elevated CRP, defined as above the median value (0.20 mg/dL), survived for an average of 19.79 months, compared with 22.79 months for those with lower CRP levels.

Results were similar in the independent cohort of 116 patients with ALS. In this group, higher CRP levels were also associated with shorter survival (hazard ratio, 1.044; 95% CI, 1.016 - 1.056; P ≤ .001). Average survival was 29.53 months for those with higher CRP levels and 37.03 months for those with lower levels.

Post Hoc Analysis of NP001 Study 

Use of the same CRP threshold as in the above studies in the post hoc analysis of the phase 2 trial of NP001 showed that patients with elevated baseline CRP levels receiving the higher dose of NP001 had significantly less functional impairment after the treatment period compared with patients with normal baseline CRP, regardless of whether patients with normal CRP levels received NP001 or placebo, the researchers report. 

"These results are  surprising as you would expect patients with high levels of inflammation to progress faster, but this study actually showed the opposite — if they had a greater burden of inflammation they progressed the slowest when on the medication," Dr Appel commented to Medscape Medical News.

He noted that NP001 has an anti-inflammatory action. "It reduces the proinflammatory state of circulating macrophages. It is believed that macrophages secrete inflammatory mediators that aggravate ALS, and NP001 is targeted to reduce this. So I think what we might be seeing is that high CRP is identifying patients with an overall proinflammatory status who would benefit most from the drug."  

In the paper, the researchers add that CRP is an in vivo activator of complement and that the complement pathway has been postulated to contribute to motor neuron disease. 

Dr Appel reported that Neuraltus is now conducting a new study of NP001 in patients with ALS who have high CRP levels, with results expected next year. "If positive, we are hopefult this treatment could be made available to patients in the future, as there are very few treatment options for ALS patients and new therapies are urgently needed," he said.

Dr Lunetta and Dr Appel report serving on a scientific advisory board for Neuraltus.   

JAMA Neurol. Published online April 3, 2017.  Abstract

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