CRP Levels Elevated in Migraine

Levels of the inflammatory marker C-reactive protein (CRP) are significantly elevated in young adults with migraine, which may not only offer insights into the pathogenesis of the condition but also point to novel therapeutic avenues, researchers say.

Delegates here at the American Headache Society (AHS) 58th Annual Scientific Meeting heard that levels of the protein, as measured on high-sensitivity CRP (hsCRP) assay, were higher by 11% in people with migraine compared with those in unaffected individuals, rising to 17% among women.

Gretchen Tietjen, MD, professor and chair of neurology and director of UTMC Headache Treatment and Research Program, University of Toledo, Ohio, and colleagues say the study findings show “a positive association between migraine diagnosis and elevated hsCRP, with a significant effect size,” particularly in young women.

Conflicting Results

Although there has been a great deal of interest in potential association between markers of inflammation and migraine, the evidence linking increased CRP levels with the condition is limited, and there have been conflicting results from population-based studies. However, it is notable that those studies were conducted in different age groups from that in the current analysis.

The researchers therefore examined data on 9269 adults aged 24 to 32 years taking part in Wave 4 of the Add Health Study, as part of which participants discussed diagnoses of migraine, depression, and anxiety with their healthcare provider. In addition, dried capillary whole blood spots were obtained from the individuals during in-home visits, on which blood hsCRP assay was performed.

The team found that 1049 (11.3%) participants reported migraine.

Linear regression analysis, taking into account sociodemographic factors, body mass index, infections, current pregnancies, subclinical symptoms, anxiety, and depression, indicated that mean hsCRP levels were significantly higher in individuals with migraine than in those without.

Specifically, participants with migraine had an hsCRP level of 5.54 ± 9.04 mg/L vs 4.40 ± 7.47 mg/L in those without migraine (P < .001).

Although women had higher mean hsCRP levels than men, the difference in levels between those with and without migraine was significantly different only in men, at 3.63 ± 6.32 mg/L vs 3.05 ± 5.25 mg/L in men (P = .03) and 6.26 ± 9.78 mg/L vs 5.75 ± 8.97 mg/L in women (P = .08).
Interestingly, when all potential confounding factors were taken into account, migraine was significantly associated with log hsCRP levels across the whole sample, at an r value of 0.11 (P = .04), and in women, at an r value of 0.17 (P = .01), but not in men (r = 0.01; P = .94).

Dr Tietjen believes that the relationship between CRP levels and migraine could be direct. “I think that it is possible that it is a consequence of having migraine, in that, when there’s changes within the brain in the endothelium, that can increase levels of things like [CRP] and inflammation,” she said.

Noting that the relationship was more pronounced in women, she added: “Whether it has something to do with endothelial activation being more easily triggered in women than in men I think is interesting, but I don’t think we can say for sure why we would see it more frequently in women than men.”

Nevertheless, Dr Tietjen said the current findings may point to therapies that target inflammation in general, and CRP levels in particular, potentially being beneficial in migraine.

She highlighted the JUPITER trial, in which the statin rosuvastatin was shown to reduce the incidence of major cardiovascular events in individuals with high CRP levels, although she acknowledged that concerns have been raised about the study’s methodology.

In addition, Catherine Buettner MD, MPH, and colleagues conducted a randomized, double-blind, placebo-controlled trial of simvastatin plus vitamin D, finding that the combination is effective for prevention of headache in adults with episodic migraine.

“Why would it be an effective migraine treatment unless something tied into the migraine pathogenesis had either something to do with cholesterol or inflammation or something that statins actually work on?” Dr Tietjen commented.

“I did think that that was very intriguing, as [CRP] might be something that would guide us as to which patients would be most likely to respond to which therapies,” she added.

Dr Tietjen concluded: “I think it’s an area ripe for more study, but I do believe that it makes sense in what we’re learning both about the importance of the endothelium potentially in migraine and the fact that we are seeing that some therapies that actually have an effect on [CRP] may be effective in migraine in a relatively young, healthy population of people.”

Commenting on these findings, Stephen Silberstein, MD, professor, Department of Neurology, Thomas Jefferson University and Jefferson Health, and director, Jefferson Headache Center, Department of Neurology, Jefferson Hospital for Neuroscience, Philadelphia, Pennsylvania, said the results “look interesting.”

However, he told Medscape Medical News that the wide overlap in the confidence intervals were “of concern” and limited the degree to which the study could be interpreted.

CRP Levels Tied to Statin Effects on Contrast Nephropathy in PRATO-ACS Analysis

In patients with non–ST-segment-elevation ACS (NSTE-ACS) who are about to undergo cardiac catheterization, early administration of high-dose rosuvastatin protects against contrast-induced acute kidney injury (AKI), especially in those with higher baseline levels of C-reactive protein (CRP), new research shows[1].

“In this series of NSTE-ACS patients, our study confirms previous clinical and experimental studies [showing that] high levels of systemic and/or local (renal) inflammation may contribute to the development of acute kidney injury after contrast medium exposure,” Dr Anna Toso (Santo Stefano Hospital, Italy) told heartwire in an email.

Moreover, it “adds another piece of information—that is, that ‘the higher the baseline CRP levels, the higher the [contrast-induced] AKI and adverse renal and cardiovascular event rates and the higher the benefits of on-admission rosuvastatin administration.’ ”

Measuring baseline CRP levels—and correlating this with other comorbidities, levels of other inflammatory markers, and the extent of myocardial damage—can identify the NSTE-ACS patients who have a higher risk of contrast-induced nephropathy, she noted.

The findings, based on data from the Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Nephropathy and Myocardial Damage in Patients With Acute Coronary Syndrome Undergoing Coronary Intervention (PRATO-ACS) study, were published online December 16, 2014 in JACC: Cardiovascular Interventions.

Looking at CRP Levels in PRATO-ACS

Previously in the PRATO-ACS randomized study, the researchers showed that statin-naive patients with NSTE-ACS who were about to undergo coronary angiography, in addition to receiving standard preventive measures (intravenous hydration, use of low- or iso-osmolar contrast media, and reduced dosages of contrast agents), early high-dose rosuvastatin reduced the risk of contrast-induce AKI and improved short- and mid-term clinical outcomes.

Other studies have suggested that systemic inflammation (evidenced by elevated CRP levels) could make the kidneys more vulnerable to local inflammation caused by iodinated contrast medium, which contributes to the development of contrast-induced acute kidney injury.

Thus, the researchers aimed to investigate how inflammation might explain the pathogenesis of AKI in the PRATO-ACS population.

PRATO-ACS had randomized 504 statin-naive patients scheduled for early invasive angiography to a statin group (40-mg rosuvastatin on admission followed by 20 mg/day) or a control group with no statins. The primary outcome was contrast-induced AKI, defined as an increase in serum creatinine of >0.5 mg/dL or >25% over the baseline value within 72 hours after the administration of contrast agent.

The study participants were stratified into tertiles according to their baseline CRP levels: <2.7 mg/L; 2.7 to <7.5 mg/L; and >7.5 mg/L.

Overall, 55 patients developed contrast-induced AKI: 17 of 252 patients (6.7%) in the statin group and 38 of 252 patients (15.1%) in the control group (odds ratio after adjustment for CRP 0.41, 95% CI 0.22–0.77; P=0.005).

Contrast-induced AKI increased with increasing tertiles of baseline CRP. Of the 55 patients who developed this complication, nine patients had the lowest CRP levels; 14 patients had intermediate CRP levels; and 32 patients had the highest levels (P=0.0001).

The beneficial effect of rosuvastatin was significant for patients in the highest CRP tertile (odds ratio 0.20, 95% CI 0.07–0.54; P=0.002).
Rosuvastatin treatment was followed by improved short-term outcomes at 30 days (acute renal failure requiring dialysis, persistent renal damage, all-cause mortality, MI, or stroke) and mid-term outcomes (death or MI at 6 months), especially in patients with high systemic inflammation at baseline.

Among patients who were in the highest baseline tertile of CRP, compared with control patients, those who received early rosuvastatin had a significantly lower rate of adverse events at 30 days (7.2% vs 17.4%, P=0.043); there was also a trend toward better outcomes at 6 months (6.02% vs 13.04%, P=0.12).

The group concludes: “Whether or not these benefits are due to the anti-inflammatory properties of rosuvastatin cannot be established on the basis of this study, but our findings represent a further reason in favor of early use of high-dose statin therapy and assessment of [CRP] in ACS patients.”

Pot Smokers Show Less Inflammation

People who smoke marijuana may have lower levels of inflammation compared with people who have never smoked it, according to new research on one marker of inflammation.

In the study, researchers examined data from more than 9,000 people on their history of marijuana use and their levels of C-reactive protein (CRP), one marker of inflammation that is frequently linked with people’s risk of heart disease.

About 40 percent of the people in the study said they had never smoked marijuana, while 48 percent reported having smoked the drug at least once in their lifetimes, but not in the past 30 days. About 12 percent (1115) said they smoked marijuana recently, or at least once in the past 30 days. The researchers found that the people who smoked in the last month had lower CRP levels than those who had never smoked the drug.


A woman smokes marijuana
The new evidence “points toward possible anti-inflammatory effects of cannabis smoking,” the authors wrote in the study, published online Nov. 28 in the journal Drug and Alcohol Dependence.

However, the researchers remain cautious about the possible implications of their findings, as previous research on CRP levels and marijuana use in people has been scarce and the results of other studies have been inconsistent. [11 Odd Facts About Marijuana]

“Replication studies always are very important, and no firm conclusions can be drawn until evidence starts to converge,” study author Omayma Alshaarawy, a postdoctoral researcher in epidemiology at Michigan State University, told Live Science.

The new study was based on data gathered from people ages 20 to 59 from the National Health and Nutrition Examination Survey (NHANES) that was collected between 2005 and 2010.

The findings come after a previous study of about 8,000 people, also ages 20 to 59, which yielded more-mixed results. The previous study found — in line with the idea that marijuana may lower inflammation — that people who had smoked marijuana in the past had lower average CRP levels than those who had never used the drug. It also found that former and current marijuana smokers were less likely to have CRP levels that would be considered “elevated” than people who had never used the drug.

However, another finding from that same study cast doubt on the notion that pot lowers inflammation, because current marijuana smokers did not have lower CRP levels than those who had never used the drug. The findings were based on NHANES data collected between 1988 and 1994, and published in 2012 in the journal BMJ Open.

And in another study of 1,420 young people (whose average age was 14), published in 2013 in the journal Drug and Alcohol Dependence, researchers found that marijuana use was actually linked to higher CRP levels.

That study, however, “was based on a relatively small sample in the Great Smoky Mountains, with relatively large margins of error,” Alshaarawy said.

In contrast, the new study “is based on quite large national samples with much smaller margins of error,” she said. “But there still is reason to postpone drawing firm conclusions until more research has been completed.”

The difference in the results of the new study and the study of the young people may have something to do with differences in the participants’ ages, said Émilie Jouanjus, a faculty member and marijuana researcher at the Toulouse University Hospital in France, who was not involved in any of the CRP studies.

Jouanjus called the new study “interesting,” saying that it adds to scientific knowledge in the field of marijuana use.

The mechanism that might underlie a link between lower CRP levels and smoking marijuana is not clear. However, based on previous research, Alshaarawy and her colleagues speculated that marijuana’s activation of cannabinoid-2 receptors could mediate the drug’s potential anti-inflammatory effects.

It also remains unknown how the drug may influence people’s risk of heart disease, which has long been linked with elevated CRP levels.

“CRP is a marker of inflammation and thus constitutes a cardiovascular risk factor,” Jouanjus said.”This implies that lower CRP levels should [theoretically] be linked to a lower risk of heart problems.”

At the same time, some reports have linked heart problems, including fatal problems, to marijuana use, particularly among young people.

“Indeed, the cardiovascular complications reported in the scientific literature mainly concern young marijuana users with apparently no cardiovascular risk factor,” Jouanjus said.

In a September 2014 interview with Live Science, Dr. Sripal Bangalore, an associate professor and interventional cardiologist at the Department of Medicine of NYU Langone Medical Center, used term “the pot heart” to describe this phenomenon.

However, the reports that link marijuana use with heart problems “offer little more than anecdotal evidence at this point,” Alshaarawy said.

Jouanjus offered a possible explanation of this seemingly conflicting information on marijuana’s potential effects on health. She said there is indeed evidence that compounds in marijuana have anti-inflammatory properties that are mediated by the activation of type 2 cannabinoid receptors. However, the compounds also target other receptors and activate pathways that may play a role in triggering cardiovascular diseases, she said.