Adalimumab targets PsO inflammation, not necessarily heart disease

A study published in the May issue of Circulation: Cardiovascular Imaging, shows that “adalimumab reduced key markers of inflammation including glycoprotein acetylation compared with phototherapy with no effect on glucose metabolism and vascular inflammation, and potential adverse effects on high-density lipoprotein.”

The researchers report adalimumab has significant anti-inflammatory effects in psoriasis patients’ skin and blood, improving systemic inflammation but without impacting vascular inflammation. Cardiometabolic disease risk increases with psoriasis severity and has been shown to reduce lifespan independently of traditional risk factors by about five years. Especially psoriasis patients with severe disease tend to have increased levels of inflammatory markers that are predictive of future cardiovascular risk, including C-reactive protein (CRP), tumor necrosis factor (TNF) alpha, interleukin (IL)6 and glycoprotein acetylation (GlycA), an emerging biomarker of systemic inflammation and cardiovascular disease. 

In this study, researchers randomized psoriasis patients to receive adalimumab (Humira, Abbvie), phototherapy or placebo for 12 weeks, with crossover to adalimumab for a total 52 weeks. They looked at treatment effects on vascular inflammation and cardiovascular biomarkers. Ninety-two patients completed the randomized controlled part of the study. And, 61 of 81 patients that entered the adalimumab extension completed 52 weeks on adalimumab.

“Our study looked at several interrelated but separate pathways towards cardiovascular events,” said Joel M. Gelfand, M.D., the study’s corresponding author of the University of Pennsylvania. “We showed that there wasn’t a negative effect, but rather a neutral effect on vascular inflammation, which is an important finding because we know that some anti-inflammatory treatments can have unanticipated effects. For example, it was thought that IL-17 inhibitors would help Crohn’s Disease, but they don’t and probably make it worse. The study is reassuring in that respect.”

There were no changes in vascular inflammation at week 12 in all groups, and at 52 weeks of adalimumab treatment.
Adalimumab and phototherapy treatment improved IL-6 and CRP inflammatory biomarkers that are known to predict cardiovascular events. Adalimumab, but not phototherapy, also reduced TNF-alpha and GlycA at weeks 12 and 52.
IL-6 worsened among those taking adalimumab by the study’s close.

Adalimumab and phototherapy had neutral effects on glucose metabolism, including metabolic markers insulin, adiponectin and leptin, during the placebo-controlled period of the study.

And, while the findings remained fairly consistent with longer-term exposure to the drug, researchers did note a negative effect from adalimumab on high-density lipoprotein, or HDL.

“We saw impairments in HDL function, as well as a decrease in HDL particle size, by 52 weeks,” Dr. Gelfand says.
Phototherapy, on the other hand, increased HDL particle size at 12 weeks.

THE STUDY IN CONTEXT
This study’s result demonstrating TNF inhibition has no impact on vascular inflammation is similar to a study in the journal Heart showing no beneficial effects of TNF inhibition in heart attack patients. [ADDED] However, previously published observational studies on TNF-alpha inhibitors suggest that psoriasis and rheumatoid arthritis patients treated with TNF-alpha inhibitors have a lower risk of cardiovascular events over time, compared to patients not treated with these agents.

“If that’s the case, our study suggests that the beneficial effect of TNF inhibitors on cardiovascular events is not being mediated by an impact on aortic vascular inflammation or its impact on lipid metabolism or glucose metabolism, but rather on these inflammatory measures, such as CRP, TNF-alpha or GlycA,” Dr. Gelfand said.

Psoriasis is associated with cardiovascular and metabolic comorbidities. In 2006, Dr. Gelfand published work in Journal of the American Medical Association that suggested moderate to severe psoriasis is linked to increased risks of cardiovascular disease and premature death.

Dermatologists should continue to emphasize the importance of screening psoriasis patients cardiovascular risk factors, including high cholesterol, elevated glucose, hypertension, smoking and obesity, he says.

“Globally we should be addressing their established cardiovascular risk factors. By controlling those, we could certainly lower their risk for cardiovascular disease,” he said.

In a study published in the Journal of the American Academy of Dermatology this year, Korean researchers reported that ustekinumab (Stelara, Janssen) for psoriasis was associated with decreased systemic and vascular inflammation related to metabolic syndrome and cardiovascular disease. University of Pennsylvania researchers found ustekinumab resulted in a 19 percent reduction in aortic inflammation in patients treated with the drug. They presented those findings at the 2018 American Academy of Dermatology annual meeting in San Diego.

The systemic effect seen from anti-TNF therapy on cardiometabolic risk in psoriasis patients offers a framework for future researchers to look at whether targeting other inflammatory pathways to treat psoriasis might improve cardiometabolic risk in these patients. [ADDED] Larger studies are needed to confirm the impacts of adalimumab treatment on cardiovascular inflammation and biomarkers, the authors write.

DISCLOSURES
This study was funded by Abbvie and the National Institutes of Health.

REFERENCE
Nehal N. Mehta, Daniel B. Shin, Aditya A. Joshi, et al. “Effect of 2 Psoriasis Treatments on Vascular Inflammation and Novel Inflammatory Cardiovascular Biomarkers.” Circulation: Cardiovascular Imaging. 2018;11:e007394. Originally published May 18, 2018 https://doi.org/10.1161/CIRCIMAGING.117.007394