The anti-inflammatory effect of anti-TNFs – drugs commonly used to treat inflammatory bowel disease (IBD) – is not limited to just the intestines. The potentially severe arterial complications promoted by the disease-related chronic inflammation are also reduced.
Chronic generalized inflammation promotes the development of atherosclerosis, itself associated with sometimes severe complications: stroke, acute coronary syndrome (ACS), peripheral artery disease (PAD), etc. In chronic inflammatory rheumatism (particularly rheumatoid arthritis), it has been established that the chronic inflammation associated with the disease increases the cardiovascular risk, whereas the anti-inflammatory treatments reduce it. However, little is known about the cardiovascular risk and impact of the treatments on this risk in inflammatory bowel diseases (IBD), namely Crohn’s disease and ulcerative colitis. The French working group BERENICE wished to conduct research in order to bridge this gap: after having reported that IBD patients had an increased risk of acute arterial events in relation to the general population, it has recently shown in a new study that anti-TNFs – one of the main treatments of IBD – also reduce the onset of acute arterial events. According to Julien Kirchgesner* who carried out this analysis, these data must be taken into account when evaluating the benefit/risk balance of anti-TNFs at the time of their prescription.
An exhaustive study thanks to population data
At the Pierre Louis Institute of Epidemiology and Public Health, Kirchgesner conducts pharmaco-epidemiological research into immune-mediated inflammatory diseases, using French medical-administrative databases as a basis: "We used the French national health data system (SNDS), which pools the outpatient treatment delivery and hospitalization data of over 98% of the general population, and whose size makes it possible to study the impact of treatment according to the various patient subgroups". In 2018, an initial consultation of the SNDS had identified an increased risk of acute arterial events (stroke, ACS, PAD) in people with IBD, compared with the rest of the population. A risk that appeared all the more substantial given the severity of the disease and young ages of the patients. "It therefore appeared interesting to evaluate whether the anti-inflammatory effect of the treatments prescribed for IBD also offered a way of reducing the complications related to atherosclerosis."
Refining the risk-benefit balance of the anti-TNFs
In this new research, all patients over 18 years of age with a pre-2012 diagnosis of IBD were identified. Data on the dispensing of anti-TNF medication and thiopurines – an older class of anti-inflammatories – were extracted. Finally, the acute arterial events (stroke, ACS, PAD) occurring over the 2010-2014 period were gathered. All in all, the data of 177,827 patients (including 50.7% with Crohn’s disease) were analyzed and provided various useful information for clinical practice: "We firstly observed the non-negligible incidence of the arterial events", with 4,145 identified for the follow-up period, i.e. 5.4 events per 1,000 person-years.
In addition, evaluation of the impact of the treatments in treated versus untreated individuals showed that anti-TNFs were associated with a 21% lower risk of cardiovascular events, whereas the thiopurines did not enable any statistically significant reduction: "We think this difference is due to the degree of remission potentially obtained with anti-TNFs, notably due to the regression of the biological inflammation markers". Indeed, the degree of remission can vary according to the treatment, from the disappearance of symptoms without complete normalization of the circulating inflammation mediators, to mucosal healing with normalization of the digestive biopsies. "This suggests that the objectives of disease remission must be ambitious in not being limited to the regression of symptoms but extended at least to biological remission." This appears to be especially true among the population of men with Crohn’s disease on anti-TNFs, for whom a 40% decrease in the event risk was observed.
"In this age of personalized medicine, it is essential to take into account the patient’s various characteristics so as to offer them a treatment with the best benefit/risk balance," explains the researcher. It therefore appears necessary to include the protective effect of the anti-TNFs in terms of acute arterial events in the benefit/risk balance of these treatments which, beyond their benefit in terms of disease remission, are linked to a risk of infection and certain cancers. "We will soon be able to supplement these data with research into the new classes of anti-inflammatories which are beginning to be indicated in IBD and whose mechanisms of action differ: the anti-integrins, the antibodies targeting IL-12 and IL-23, the Janus kinase inhibitors, etc. As such, we will be able to supplement knowledge of the risk/benefit balance of the various IBD treatments and evaluate in particular whether their cardiovascular benefits are similar to or differ from those of the anti-TNFs."
*unit 1136 Inserm/Sorbonne Université, Pharmacoepidemiology and healthcare assessment team, Pierre Louis Institute of Epidemiology and Public Health, Paris
Source : Kirchgesner J et al. Risk of acute arterial events associated with treatment of inflammatory bowel diseases: nationwide French cohort study. Gut, August 24, 2019. DOI: 10.1136/gutjnl-2019-318932