Immune Modulation of Coronary Atherosclerosis with Anti-Cytokine Treatment

There is accumulating evidence that inflammation and auto-immunity significantly impact atheroprogression and cardiovascular morbidity.^1–6 As early as 1959 the idea of leveraging active or passive immunity to modulate atherosclerosis and mitigate cardiovascular disease morbidity has been postulated.⁷ Since then overwhelming basic and translational evidence shows that arterial wall lipoprotein uptake and impaired cholesterol efflux leads to accumulation of foam cells and the release of pro-inflammatory cytokines, such as interleukin-1-alpha (IL-1α), IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α).^{3, 5, 8, 9} As a result, these factors illicit a cascade of both cellular and humoral tissue consequences that lead to arterial wall damage, plaque progression, and subsequent plaque rupture.^{3, 5, 9, 10}

Auto-immune disorders such rheumatoid arthritis, lupus erythermatosus, antiphospholipid syndrome, and psoriasis, are characterized by increased systemic production of inflammatory cytokines and circulating autoantibodies.² Early evidence suggested that individuals with underlying pro-inflammatory states are at higher risk of atherosclerosis and a higher prevalence of cardiovascular disease.^11–13 More recently clinical trial evidence suggests that circulating pro-inflammatory cytokines and autoantibodies can indeed contribute to atheroprogression and cardiovascular pathology.^{2, 14, 15} The study by Choi et al. adds to this body of evidence and highlights that individuals with more severe psoriasis (as determined by psoriasis area severity index; PASI) are more likely to have higher lipid-rich necrotic core (LRNC) coronary plaque areas.¹⁶ Importantly, 124 patients with psoriasis that received biologic therapy with TNF-α inhibitors (adalimumab and etanercept), IL-12/23 inhibitor (ustekinumab), and IL-17 inhibitors (ixekizumab and secukinumab) had significantly less progression in LRNC over a 1-year observational period compared to 85 patients that received standard non-biologic therapy.¹⁶ These observations are exciting yet raise multiple new avenues of future investigation, including the proposed need for a randomized prospective trial to evaluate the role of anti-cytokine psoriasis treatments in patients who are higher risk of coronary plaque progression.

The anti-inflammatory effects of cholesterol-lowering HMG-CoA reductase inhibitors, such as statins, alone is insufficient to blunt major adverse cardiovascular events in at risk populations. Although initially the JUPITER trial demonstrated a 44% risk in first ever cardiovascular events in healthy volunteers treated with rousuvastatin, subsequent studies demonstrated that atherosclerotic events continue to occur at alarmingly high rates in individuals chronically treated with statins.¹⁷ This suggested that residual inflammatory risk may be an important persistent risk factor in individuals who are at higher risk of disease progression. In support of this the PROVE-IT trial demonstrated that 29% of individuals with preceding acute coronary syndrome (ACS) who were treated with atorvastatin still had residual inflammatory risk (high sensitivity C-reactive protein; hsCRP > 2mg/L).¹⁸ Similarly, the IMPROVE-IT study demonstrated that individuals with stable ACS who were treated with combination therapy of simvastatin and ezetimibe, had lowered residual inflammatory risk and composite cardiovascular morbidity events.¹⁹ In summary, it was evident from these trials that residual inflammation in arteries represents a significant risk for continued disease progression despite statin therapy. As a result current opinions believe that arteries may represent arterial tertiary lymphoid organs (ALTO) that may, and should, be targeted with immune-modulators.²⁰

The effect of various immune-modulators on atherosclerotic plaque progression has been tested with varying levels of clinical trial success.^21–23 The CIRT trial randomized individuals with stable atherosclerosis to low-dose methotrexate versus placebo and observed no significant difference in circulating levels of IL-1β, IL-6, and CRP.²⁴ However, the CANTOS trial, randomized individuals to treatment with canakinumab, an anti-inflammatory therapy targeting IL-1β innate immunity, and observed significantly reduced cardiovascular events that were independent of lipid-levels and blood pressure.²⁵ The observations in CIRT, CANTOS, and other trials highlights the importance of considering the mechanistic diversity of the ALTO inflammasome and how this contributes to disease progression. So far, in randomized trials, only targeting the IL-1β and IL-6 pathways with canakinumab has proven effective in reducing cardiovascular event rates.^{8, 25} As the Choi et al. study demonstrated, it is recognized that other anti-cytokine agents that intersect with ALTO signaling may also provide similar significant benefits to at risk populations.

The Choi et al. study also describes the use of histopathological CCTA imaging for in vivo coronary plaque characterization in a longitudinal fashion. These image-based analyses were performed using a commercially available plaque quantification software (vascuCAP, Elucid Bioimaging Inc., Boston, MA).¹⁶ Similar CT and MRI-based analysis techniques have been previously reported, and collectively provide promising tissue-specific characterization techniques that can be used to complement objective clinical endpoints.^26–28 In this study, LRNC was observed to have a strong positive correlation with subject Framingham risk score and hypertension, thus potentially supporting the technique’s validity in at risk populations. It is also worth noting that although circulating serum biomarkers such as hsCRP and GlycA seemed to decrease following 1 year of biologic therapy, unlike CCTA-mediated LRNC analysis, they were not different between patients treated with or without biologic therapy.¹⁶ Hence, future clinical trials evaluating immune modulation of coronary atherosclerosis should consider implementation of CCTA analysis for more sensitive evaluation of disease patterns within the artery itself.

Although the Choi et al. study provides a new perspective on the impact of psoriasis treatments on coronary plaque progression, the study admittedly has some notable limitations.¹⁶ Firstly, the study was limited to mostly middle-aged male subjects, and other vital racial/social demographics were not reported in the study. It remains unclear to what extent gender is associated with auto-immune-mediated atherosclerosis, but various studies have suggested a higher prevalence of disease among females.²⁹ Second, although BMI was relatively similar between patients treated with biologic and non-biologic therapy there was also no indication of whether diet and exercise regimens differed between the study groups. Further, it was clear in this observational intention-to-treat study, sampling bias exists as patients with more PASI were more likely to receive biological therapy. Although this raises concerns about the validity of the study findings, it also argues that if PASI was more evenly distributed, the change in LRNC could have been potentially even greater in the biological therapy group.¹⁶ Lastly, like coronary plaque progression, atherosclerosis in other vascular beds, such as the carotid arteries and peripheral arteries of the lower extremities may certainly be similarly impacted by psoriasis anti-cytokine treatments.²¹ Certainly further studies merit focused investigation of the peripheral arterial system in addition to the coronary arteries given the high prevalence of disease in our aging global populations.³⁰