World-class research. Ultimate impact.
More on impact ›

Opinion ARTICLE

Front. Cardiovasc. Med., 02 July 2019 | https://doi.org/10.3389/fcvm.2019.00090

New Promises and Challenges on Inflammation and Atherosclerosis: Insights From CANTOS and CIRT Trials

  • 1Helium-3 Biotech, South Perth, WA, Australia
  • 2Faculty of Health Sciences, School of Pharmacy and Biomedical Science, Curtin University, Perth, WA, Australia

Atherosclerosis is still a great burden on human health and scientific achievements of the past 30 years have definitively proven the inflammatory causes of the disease (1, 2) highlighted by the results of the CANTOS trial (3). Canakinumab inhibition of interleukin-1 (IL1)-beta has been demonstrated to provide protection against cardiovascular (CV) risk irrespective of lipid levels in a cohort of patients with high C–reactive protein (CRP) levels despite achieving blood lipid control, as measured by high sensitivity C-Reactive Protein (hsCRP) (3).

The final demonstration of atherosclerosis as an inflammatory-driven pathology is driving research toward new anti-inflammatory approaches that could influence the natural history of the disease and change the clinical paradigms of therapy. Considering the costs of canakinumab and exploiting different avenues of anti-inflammatory therapies, a more affordable approach has been proposed by the authors of the CANTOS study (4). Low dose methotrexate (MTX) proposed in the CIRT study (5) could be an alternative approach aimed to lower the inflammatory burden and to deliver a beneficial effect on patient CV risk (4). Data from this study is now available (5) and demonstrates the feasibility of the low MTX treatment and at the same time a somewhat surprising lack of effect on CV risk.

In this published randomized trial low dose MTX did not reduce IL1-beta levels or hsCRP and did not have any meaningful effect on cardiovascular disease (CVD) risk (a slight increase in skin tumors was registered over time in the MTX treated population).

These results, while disappointing, are not entirely unexpected: MTX activity and the molecular pathways involved are different from the canakinumab mechanism(s) of action, targeting less relevant pathogenic signal cascades in atherosclerosis. Of note the CIRT trial was to a large extent based on the data from patients affected by Rheumatoid Arthritis (RA) on low dose MTX in whom (as observed) was shown to decrease both CV risk and inflammatory cytokine levels (4, 68). The genesis of atherosclerotic lesions in RA remains an open and unsolved line of enquiry for further research: Is atheromata driven by the same mechanism as classical atherosclerosis or is there a disparate molecular pathway hidden among the CV framework? Maybe a greater extent of T cell involvement could be a possible cause but only further research and observation will deliver the dataset required. There is indeed mounting evidence that T cell subpopulations are involved in the pathogenesis of atherosclerosis (9). Thus, in principle, we should be cautious in comparing the results of the two trials without considering the differences in pathways and biological response.

This caveat notwithstanding, what are the hallmarks that we could extrapolate from this nevertheless very interesting study?

The first consideration is related to the target population of each study (CANTOS and CIRT): as highlighted by the authors (5) both trials involved heavily pre-treated subjects and prior randomization, but the two populations used for CANTOS and the CIRT study were actually different and not superimposable.

CANTOS included patients after myocardial infarction (MI) with residual inflammatory risk as measured by hsCRP levels higher than 2 mg/L despite aggressive therapy. CIRT had patients with indirect evidence of inflammatory risk (not defined by hsCRP levels) determined by the presence of diabetes or metabolic syndrome (pathologies associated with a pro-inflammatory pabulum). Levels of hsCRP were 4.2 mg/L as a median baseline in CANTOS, whereas the median hsCRP level was 1.6 mg/L at randomization in the CIRT population (3, 5).

Thus, in the CANTOS trial the pro-inflammatory pabulum was definitely more pronounced (as per hsCRP levels) and this situation could in part explain the different results of the two studies.

Although both trials studied a high risk population, the event rates for the same primary endpoint, a composite of non-fatal MI, non-fatal stroke and CV death were considerably higher in CANTOS (4.5/100 person years) compared with CIRT (3.43/100 person years). As an interesting point of fact, CIRT event rates were at the level of those patients achieving an hsCRP < 2mg/L with canakinumab in CANTOS (3.28/100 person years). Median hsCRP levels in CIRT were indeed lower than in the CANTOS placebo arm (as reported above).

Regarding MTX mechanisms of action, it has been reported that MTX decreases elevated CV risk in patients with RA, along with suppression of elevated CRP levels [CRP being less sensitive and precise than hsCRP; (6, 7)]. So, it seems that the inflammatory burden in the overall CIRT study population may not have exceeded a certain threshold to benefit from anti-inflammatory therapies, thus a positive role of MTX in vascular wall disease is not entirely ruled out (68). These assumptions are highlighted by the fact that we do not really know the exact mechanism of action with low dose MTX (10): the most stringent experimental proof is an increase in adenosine (an important anti-inflammatory mediator) and adenosine-related metabolite levels in treated patients (10) and other possible mechanisms of action are proposed (10). At this time, it is not known if the proposed mechanism(s) of action of low dose MTX are relevant or scarcely relevant to the pathogenesis of atherosclerosis or relevant only in some stages of the disease. More studies focusing on the role of T lymphocytes and adaptive immunity (9) in the natural history and pathogenesis of atherosclerosis are warranted to better understand the molecular action(s) and the eventual role of low dose MTX.

A secondary and important aspect is that targeted inhibition of inflammatory pathways is warranted in the case of atherosclerosis for a significant therapeutic effect.

It is worth noting that in the CANTOS trial a definitive reduction in Interleukin-6 (IL6) and hsCRP levels (known inflammatory biomarkers downstream to IL1-beta signaling pathway) were substantial, whereas no changes were registered in the CIRT study.

It is conceivable that robust reduction of CV risk is dependent on the specific pathways targeted. Of note, recent experimental results on the involvement of the NLRP3 pathway (a main trigger of IL1-beta release) seems to confirm the pivotal role of specific signaling pro-inflammatory routes in atherosclerosis pathophysiology (1113). NLRP3 pathway inhibition could indeed effectively target inflammatory pathways in atherosclerosis (1113). In this scenario it is interesting to report the recent Novartis withdrawal of EU filing for approval of canakinumab for CV risk reduction; the FDA had rejected their application for the US market as well1. According to the available reports the regulatory agencies were still concerned that the beneficial effects might not outweigh the increased risk of serious infections [see also (1416)]. This is noteworthy since canakinumab did reduce the overall CV mortality rate by about 30% in patients that responded with a reduction in hsCRP and IL6 after the first injection. “Non-responders” could conveniently be identified by one follow-up hsCRP measurement at 3 months and treatment could be terminated in these patients sparing them the risk of experiencing serious side effects. In “responders (hsCRP < 2 mg/L)” the benefits obviously outweigh the risks resulting in an astonishing NNT (Number–Needed to Treat) of 16! Based on this data we are of the opinion that the research community needs to scrutinize the decisions being made by the regulatory authorities (under exclusion of the public) across the scientific literature; as this research sparks further critical discussions, so too will other reviews cause different interpretations of the data. Other specialists in the field of Internal Medicine (such as rheumatologists) are used to suppress the immune system to alleviate rheumatic and autoimmune disease burden while balancing the risk for infections. There is no reason to believe that cardiologists would not be able to make comparable judgements based on that data. Thus, the risk of serious adverse infectious effects related to canakinumab use is clear, but we think that it could be manageable with careful patient selection (i.e., excluding in future studies patients with diabetes mellitus), and with a multi-specialist approach to CV patients with a residual inflammatory “pabulum.” New approaches (such as the NLRP3 inhibition mentioned above) may be a possible solution in delivering therapeutic specificity and efficacy while protecting patients from serious adverse side effects.

In conclusion, we have to be grateful for the authors of the CANTOS and CIRT studies who both delivered important information to the medical community in regards to the pathogenic mechanisms of atherosclerosis and its potential clinical translations. Understanding differences and caveats in the CANTOS, CIRT, and other studies involving additional anti-inflammatory therapies for CVD (1420) is likely to be useful in designing future therapeutics for atherosclerosis. Critically, more studies are needed and it is not yet time for a robust clinical application of these findings, but the CANTOS and CIRT trials have paved the way for new personalized and promising avenues for controlling this still devastating disease.

Author Contributions

RP: literature review, an advanced draft of the manuscript, final editing, review, and approval of the manuscript. MV: idealization and scientific input, literature review, an initial draft of the manuscript, final review, and approval of the manuscript.

Conflict of Interest Statement

RP is Chief Scientific Officer of Helium-3 Biotech.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

References

1. Ross R. Atherosclerosis- an inflammatory disease. N Engl J Med. (1999) 340:115–26. doi: 10.1056/NEJM199901143400207

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Hansson GK. Inflammation and atherosclerosis. The end of a controversy. Circulation. (2017) 136:1875–7. doi: 10.1161/CIRCULATIONAHA.117.030484

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Ridker PM, Everett B, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. CANTOS trial group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. (2017) 377:1119–31. doi: 10.1056/NEJMoa1707914

CrossRef Full Text | Google Scholar

4. Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, et al. Rationale and design of the cardiovascular inflammation reduction trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J. (2013) 166:199–207. doi: 10.1016/j.ahj.2013.03.018

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, et al., Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. (2019) 380:752–62. doi: 10.1056/NEJMoa1809798

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Hwang YG, Balasubramani GK, Metes ID, Levesque MC, Bridges SL Jr, Moreland LW. Differential response of serum amyloid A to different therapies in early rheumatoid arthritis and its potential value as a disease activity biomarker. Arthritis Res Ther. (2016) 18:108. doi: 10.1186/s13075-016-1009-y

CrossRef Full Text | Google Scholar

7. Ismaili H, Ismaili L, Rexhepi M. Values and correlations between C-reactive protein and apolipoprotein B after treatment with methotrexate at patients with rheumatoid arthritis. Open Access Maced J Med Sci. (2019) 7:1293–8. doi: 10.3889/oamjms.2019.278

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Nishina N, Kaneko Y, Kameda H, Kuwana M, Takeuchi T. Reduction of plasma IL-6 but not TNF-α by methotrexate in patients with early rheumatoid arthritis: a potential biomarker for radiographic progression. Clin Rheumatol. (2013) 32:1661–6. doi: 10.1007/s10067-013-2309-0

CrossRef Full Text | Google Scholar

9. Tabas I, Lichtman AH. Monocyte-macrophages and T cells in atherosclerosis. Immunity. (2017) 47:621–34. doi: 10.1016/j.immuni.2017.09.008

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Brown PM, Pratt AG, Isaacs JD. Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers. Nat Rev Rheumatol. (2016) 12:731–42. doi: 10.1038/nrrheum.2016.175

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Toldo S, Abbate A. The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol. (2018) 15:203–14. doi: 10.1038/nrcardio.2017.161

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Wang Z, Hu W, Lu C, Ma Z, Jiang S, Gu C, et al. Targeting NLRP3 (Nucleotide-Binding Domain, Leucin-Rich-Containing Family, Pyrin Domain-Containing-3) inflammasome in cardiovascular disorders. Arterioscler Thromb Vasc Biol. (2018) 38:2765–79. doi: 10.1161/ATVBAHA.118.311916

CrossRef Full Text | Google Scholar

13. Baldrighi M, Mallat Z, Li X. NLRP3 inflammasome pathways in atherosclerosis. Atherosclerosis. (2017) 267:127–38. doi: 10.1016/j.atherosclerosis.2017.10.027

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Weber C, von Hundelshausen P. CANTOS trial validates the inflammatory pathogenesis of atherosclerosis. Setting the Stage for a New Chapter in Therapeutic Targeting. Circ Res. (2017) 121:1119–21. doi: 10.1161/CIRCRESAHA.117.311984

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Ridker PM. Clinician's guide to reducing inflammation to reduce atherothrombotic risk. J. Am Coll Cardiol. (2018) 72:3320–31. doi: 10.1016/j.jacc.2018.06.082

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Zhao TX, Mallat Z. Targeting the immune system in atherosclerosis. J. Am Coll Cardiol. (2019) 73:1691–706. doi: 10.1016/j.jacc.2018.12.083

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Kottoor SJ, Arora RR. The utility of anti-inflammatory agents in cardiovascular disease: a novel perspective on the treatment of atherosclerosis. J Cardiovasc Pharmacol Ther. (2018) 23:483–93. doi: 10.1177/1074248418778548

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Nidorf SM, Thompson PL. Why colchicine should be considered for secondary prevention of atherosclerosis: an overview. Clin Ther. (2019) 41:41–8. doi: 10.1016/j.clinthera.2018.11.016

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Aday AW, Ridker PM. Targeting residual inflammatory risk: a shifting paradigm for atherosclerotic disease. Front Cardiovasc Med. (2019) 6:16. doi: 10.3389/fcvm.2019.00016

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Ridker PM. Anticytokine agents: targeting interleukin signaling pathways for the treatment of atherothrombosis. Circ Res. (2019) 124:437–50. doi: 10.1161/CIRCRESAHA.118.313129

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: cardiovascular risk, acute coronary syndrome, atherosclerosis, ischemic heart disease, vascular disease

Citation: Palmer RD and Vaccarezza M (2019) New Promises and Challenges on Inflammation and Atherosclerosis: Insights From CANTOS and CIRT Trials. Front. Cardiovasc. Med. 6:90. doi: 10.3389/fcvm.2019.00090

Received: 23 April 2019; Accepted: 19 June 2019;
Published: 02 July 2019.

Edited by:

Philipp von Hundelshausen, Ludwig Maximilian University of Munich, Germany

Reviewed by:

Aaron Weldon Aday, Vanderbilt University Medical Center, United States

Copyright © 2019 Palmer and Vaccarezza. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Mauro Vaccarezza, mauro.vaccarezza@curtin.edu.au