Study Supports Newest Indication for IL6R Blockade in Giant Cell Arteritis

Megan Brooks

August 17, 2018

New research confirms the association of a common variant in the gene that encodes the receptor for interleukin-6 (IL6R) with reduced risk for aortic aneurysms and supports the newest indication for IL6R blockade, giant cell arteritis, of which a major complication is aortic aneurysm, researchers say.

Katherine Liao, MD, MPH, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, and colleagues conclude that their research also highlights the promise of the phenome-wide association study (PheWAS) to leverage electronic health record data to query potential effects of new drugs in cases in which the drug mechanism of action has a clear link with a genetic variant.

Their report is published online August 8 in JAMA Cardiology.  

The Asp358Ala IL6R genetic variant is believed to impair IL6R signaling and dampen inflammation, the researchers note. Individuals with this IL6R variant who are not receiving IL6R-blocking therapy have biomarker profiles similar to those in patients treated with the IL6R blockers tocilizumab (Actemra, Genentech) and sarilumab (Kevzara, Sanofi Genzyme and Regeneron). Both are indicated for the treatment of rheumatoid arthritis, and tocilizumab is indicated for giant cell arteritis.

In a proof-of-concept study, Liao and colleagues performed a PheWAS on the Asp235Ala IL6R genetic variant to see if they could detect known effects for IL6R blockade, as well as known off-target effects from clinical trials, using data from the Million Veteran Program (MVP), a large US-based biobank of 332,799 US veterans.

They found 22 significant phenotypes associated with the IL6R genetic variant, of which 13 (59%) were associated with vascular and cardiac disease.

The IL6R variant was most strongly associated with a reduced risk for aortic aneurysm, abdominal aortic aneurysm (AAA), and aneurysm of iliac artery, as well as coronary atherosclerosis and ischemic heart disease.  

Table. Risk for Outcomes Associated With IL6R Gene Variant

Endpoint Odds Ratio (95% Confidence Interval)
Aortic aneurysm 0.90 (0.87 - 0.93)
AAA 0.87 (0.84 - 0.90)
Aneurysm of iliac artery 0.83 (0.75 - 0.92)
Coronary atherosclerosis and ischemic heart disease 0.95 (0.94 - 0.97)


That the strongest association observed was a reduced risk for aortic aneurysm is in line with the newest indication for IL6R blockade in giant cell arteritis, in which aortic aneurysm can be a presenting sign, the researchers note.

"The findings of associations with different subphenotypes of aneurysms, such as AAA and aneurysm of the iliac artery, suggest that the beneficial effects of IL6R antagonist therapy may extend beyond treatment for aneurysms associated with large vessel vasculitis," they point out.

The reduced risk for aortic aneurysms among those with the IL6R variant in the MVP was replicated in the Vanderbilt University Biobank, with 13,835 patients from a tertiary care center. The reduced risk for coronary heart disease was replicated in the UK Biobank, with 408,455 individuals from the general UK population.

"Our findings support previous studies of reduced risk for coronary heart disease with IL6R blockade, and ongoing clinical trials may validate these findings," Liao and colleagues write.

Additionally, the IL6R PheWAS identified expected drug effects, such as reduction in C-reactive protein level, as well as known off-target effects of IL6R blockade observed from clinical trials of tocilizumab and sarilumab, including associations with higher hemoglobin levels and atopic dermatitis, the researchers report.

The PheWAS approach using large biobanks and genetics is a "promising tool to assess potential beneficial and adverse effects of therapeutic agents with known pathways and related genes," they conclude.

The study had no commercial funding. The authors have disclosed no relevant financial relationships.

JAMA Cardiol. Published online August 8, 2018. Abstract

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