Anti-inflammatory Therapy in Rheumatoid Arthritis to Improve Cardiovascular Outcome

Abstract

Inflammation plays an important role in the pathogenesis of atherosclerosis and acute coronary syndromes.1Azar R.R. Waters D.D. The inflammatory etiology of unstable angina.Am Heart J. 1996; 132: 1101-1106Crossref PubMed Scopus (38) Google Scholar Pathology specimens of coronary atheroma support the concept that atherosclerosis is a chronic inflammatory process.2Ross R. Atherosclerosis- an inflammatory disease.N Engl J Med. 1999; 340: 115-126Crossref PubMed Scopus (18413) Google Scholar White cells are abundantly present in the atherosclerotic plaque, where they not only contribute to active plaque growth leading to narrowing and obstruction of the arterial lumen but also directly undermine the integrity of the fibrous cap, resulting in plaque rupture.1Azar R.R. Waters D.D. The inflammatory etiology of unstable angina.Am Heart J. 1996; 132: 1101-1106Crossref PubMed Scopus (38) Google Scholar,2Ross R. Atherosclerosis- an inflammatory disease.N Engl J Med. 1999; 340: 115-126Crossref PubMed Scopus (18413) Google Scholar Through their interaction with platelets and their secretion of procoagulant factors, leucocytes contribute to thrombosis and acute ischemic syndromes.2Ross R. Atherosclerosis- an inflammatory disease.N Engl J Med. 1999; 340: 115-126Crossref PubMed Scopus (18413) Google Scholar Epidemiologic studies also support the central role of inflammation in atherosclerosis. High-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) blood levels are independently associated with future cardiovascular events in healthy individuals without apparent cardiovascular disease, as well as in those with acute coronary syndromes.3Ridker P.M. High-sensitivity C-reactive protein: potential adjuct for global risk assessment in the primary prevention of cardiovascular disease.Circulation. 2001; 103: 1813-1818Crossref PubMed Scopus (1176) Google Scholar,4Blake G.J. Ridker P.M. C-reactive protein and other inflammatory risk markers in acute coronary syndromes.J Am Coll Cardiol. 2003; 41: 37-42Crossref PubMed Google Scholar Rheumatoid arthritis (RA) is a natural model of chronic inflammation. Patients with RA are at increased risk of adverse cardiovascular events. A recent meta-analysis of 24 observational studies reported a 59% higher risk of coronary artery disease-related mortality in patients with RA compared with the general population.5Aviña-Zubieta J.A. Choi H.K. Sadatsafavi M. Etminan M. Esdaile J.M. Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies.Arthritis Rheum. 2008; 59: 1690-1697Crossref PubMed Scopus (917) Google Scholar The risk increases well before patients develop full-blown RA.6Maradit-Kremers H. Crowson C.S. et al.Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study.Arthritis Rheum. 2005; 52: 402-411Crossref PubMed Scopus (718) Google Scholar New disease-modifying antirheumatic drugs (DMARDs) are now available for the treatment of RA and work by effectively and selectively blocking several inflammatory pathways, leading to improvement in joint symptoms. Given the central role of inflammation in atherosclerosis, these drugs might be expected to reduce adverse cardiovascular events. This issue was addressed by Hsieh et al. in this issue of the Canadian Journal of Cardiology.7Hsieh M.J. Lee C.H. Tsai M.L. et al.Biological agents reduce cardiovascular events in rheumatoid arthritis non-responsive to tumor necrosis factor-inhibitors: a national cohort study.Can J Cardiol. 2020; 36: 1739-1746Scopus (4) Google Scholar They evaluated the 2-year cardiovascular outcome in a retrospective cohort of 1584 patients from the National Health Institute database in Taiwan, who were newly diagnosed with RA and who received 1 of the 3 second-line biological agents (rituximab, tocilizumab, or abatacept) because of a poor initial response to tumour necrosis factor (TNF)-α antagonists. These 3 agents inhibit the inflammatory cascade through different pathways: Rituximab and abatacept inhibit B- and T-lymphocytes, respectively, whereas tocilizumab blocks the IL-6 pathway. The authors report that compared with rituximab, both tocilizumab and abatacept reduced the rate of occurrence of major adverse cardiovascular events (myocardial infarction [MI], stroke, heart failure, and cardiovascular death) as well as all-cause mortality in crude and adjusted multivariate analyses. Although the advantage of tocilizumab was mainly derived from reduction of nonfatal occurrence of MI, that of abatacept was mainly due to reduction of stroke and heart failure events. These findings may be valuable in selecting a second line agent for patients with RA who fail first-line therapy. They also suggest that cardiovascular benefit may depend on the specific inflammatory pathway inhibited by the drug. Although interesting, the results of this study raise several questions. First, is there evidence that selective anti-inflammatory therapy improves cardiovascular outcome in high-risk patients without overt inflammation? Second, is there similar evidence in patients with RA or other rheumatic inflammatory conditions? And, third, how solid are the results of the current study and how do they compare with those of other trials assessing biological DMRAD in RA? Three randomized prospective large-scale clinical trials testing the efficacy of specific anti-inflammatory therapy in patients with known coronary artery disease were recently published. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), showed for the first time, in a rigourous prospective randomized, double-blind placebo-controlled study that selective inhibition of the interleukin-1B (IL-1B) receptor with a monoclonal antibody reduces the composite endpoint of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death in patients with previous MI and persistently elevated hs-CRP above 2 mg/L.8Ridker P.M. Thuren E.T. MacFadyen J.G. et al.for the CANTOS Trial GroupAntiinflammatory therapy with canakinumab for atherosclerotic disease.N Engl J Med. 2017; 377: 1119-1131Crossref PubMed Scopus (3220) Google Scholar Similarly, the prospective multicentre Colchicine Cardiovascular Outcomes Trial (COLCOT) demonstrated that anti-inflammatory therapy with low-dose colchicine started within 30 days after acute MI reduces a similar composite endpoint of cardiovascular death, resuscitated cardiac arrest, nonfatal MI, nonfatal stroke, or hospitalization for angina requiring coronary revascularization.9Tardif J.C. Kouz S. Waters D.D. et al.Efficacy and safety of low-dose colchicine after myocardial infarction.N Engl J Med. 2019; 381: 2497-2505Crossref PubMed Scopus (560) Google Scholar The effects of the 2 drugs on each component of the primary composite endpoint were however, different. Canakinumab mainly reduced rate of recurrent MI, whereas colchicine lowered rate of stroke. Both therapies resulted in a reduction of angina hospitalization, requiring revascularization. In CANTOS, IL-6, and hs-CRP blood levels were significantly reduced, and cardiovascular benefit was more important in patients with the greatest reduction. However, hs-CRP level did not decrease more than placebo in a small subgroup of COLCOT in which this marker was measured. Contrary to this, the Cardiovascular Inflammation Reduction Trial (CIRT) using low-dose methotrexate was neutral.10Ridker P.M. Everett B.M. Pradhan A. et al.Low-dose methotrexate for the prevention of atherosclerotic events.N Engl J Med. 2019; 380: 752-762Crossref PubMed Scopus (440) Google Scholar After a median follow-up of 2.3 years, the incidence of the primary composite endpoint of nonfatal MI, nonfatal stroke, hospitalization for unstable angina that led to urgent revascularization or cardiovascular death was the same in the low-dose methotrexate as in the placebo group (4.13 vs 4.31 person-years, respectively). Contrary to canakinumab, methotrexate did not lower blood levels of IL-1B, IL-6, and hs-CRP. This observation has led to the hypothesis that all inflammatory pathways are not equal in term of atherothrombosis and that inhibition of the NLRP3 inflammasome,11Ridker P.M. From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for athero-protection.Circ Res. 2016; 118: 145-156Crossref PubMed Scopus (391) Google Scholar as can be achieved with both canakinumab and colchicine, seems to be the most promising target in term of reducing cardiac events. Methotrexate is a DMARD anti-inflammatory agent, broadly used in the treatment of RA.12Cronstein B.N. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis.Pharmacol Rev. 2005; 57: 163-172Crossref PubMed Scopus (420) Google Scholar In nonrandomized studies, methotrexate was shown to have a favourable cardiovascular profile compared with nonbiological DMARD. A recent meta-analysis of 10 observational cohorts of patients with RA, psoriasis, or polyarthritis found that methotrexate was associated with a 21% lower risk of total cardiovascular events and an 18% lower risk of MI.13Micha R. Imamura F. von Ballmoos W.V. et al.Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease.Am J Cardiol. 2011; 108: 1362-1370Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar Methotrexate was also associated with reduction in inflammatory biomarkers such as hs-CRP, IL-6, and TNF-α.14Solomon D.H. Goodson N.J. Katz J.N. et al.Patterns of cardiovascular risk in rheumatoid arthritis.Ann Rheumatic Dis. 2006; 65: 1608-1612Crossref PubMed Scopus (294) Google Scholar These positive findings were, however, not confirmed in the randomized trial CIRT.10Ridker P.M. Everett B.M. Pradhan A. et al.Low-dose methotrexate for the prevention of atherosclerotic events.N Engl J Med. 2019; 380: 752-762Crossref PubMed Scopus (440) Google Scholar Whether the discrepancy between observational studies and CIRT is due to a bias induced by unmeasured confounders remains open to speculation. A more likely explanation could be related to the much higher degree of inflammation present in patients with RA and the ability of methotrexate to reduce its flares rather than to suppress chronic low-grade inflammation. Similar to methotrexate, TNF-α antagonists are biological DMARD that significantly decrease levels of proinflammatory cytokines in synovial tissue and in the systemic circulation and improve symptoms of RA.15Feldmann M. Maini R.N. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?.Annu Rev Immunol. 2001; 19: 163-196Crossref PubMed Scopus (1108) Google Scholar In a cohort of 10,156 patients with RA, cardiovascular outcome was compared among 3 groups of treatments: TNF-α antagonists, methotrexate, and nonmethotrexate, nonbiological DMARD.16Greenberg J.D. Kremer J.M. Curtis J.R. et al.on behalf of the CORRONA Investigators. Tumor necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis.Ann Rheum Dis. 2011; 70: 576-582Crossref PubMed Scopus (256) Google Scholar The study found that TNF-α antagonists, but not methotrexate, was associated with a greater than 2-fold reduction in cardiovascular risk compared with nonbiological DMARD, with a dose-dependent increased risk among patients prescribed prednisone. However, in the most recent meta-analysis of 28 RA studies, both TNF antagonists and methotrexate were found to decrease risk of all cardiovascular events (relative risk [RR] 0.7; 95% confidence interval [CI], 0.54-0.9 and RR 0.72; 95% CI, 0.57-0.91, respectively), whereas nonsteroidal anti-inflammatory drugs and corticosteroids increased that risk.17Roubille C. Richer V. Starnino T. et al.The effects of tumour necrosis factor inhibitors methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis.Ann Rheum Dis. 2015; 74: 480-489Crossref PubMed Scopus (440) Google Scholar Several other studies have compared the cardiovascular safety of rituximab, tocilizumab, abatacept, and TNF-α antagonists in patients with RA. Contrary to the current analysis, these studies reported that rituximab, tocilizumab, and abatacept are equal in term of cardiovascular outcome. Two of these studies are worth noting. The first is a recent analysis of a large US cohort of 88,463 patients that included assessment of RA disease activity using the multibiomarker disease activity score (not evaluated in the current paper).18Xie F. Yun H. Levitan E.B. Muntner P. Curtis J.R. Tocilizumab and the risk for cardiovascular disease: a direct comparison among biologic disease-modifying antirheumatic drugs for rheumatoid arthritis patients.Arthritis Care Res. 2019; 71: 1004-1018Crossref Scopus (26) Google Scholar Compared with tocilizumab, the adjusted hazard ratios for the composite outcome of myocardial infarction, stroke, or cardiovascular death was 1.16 (0.89-1.53) for rituximab and 1.01 (0.79-1.28) for abatacept. The second study is a network meta-analysis of 19 studies comparing biological agents.19Castagné B. Viprey M. Martin J. Schott A.M. Cucherat M. Soubrier M. Cardiovascular safety of tocilizumab: a systematic review and network meta-analysis.PLoS One. 2019; 14e0220178Crossref PubMed Scopus (24) Google Scholar The primary outcome of MI, peripheral vascular disease, and heart failure was similar in rituximab-, tocilizumab- and abatacept-treated patients. The inferiority of rituximab in the current analysis could be explained by the different patient population, characterized by resistance to TNF-α antagonists. Alternatively, given the retrospective nature of the study, the lack of data on some important risk factors such as smoking, lipid and blood pressure levels, and differences in other important clinical characteristics of patients in the 3 groups, the result could also derive from confounding variables not accounted for in the multivariate analysis. Patients with RA are at high risk for future cardiovascular events. Nonrandomized studies point toward a favourable effect of anti-inflammatory therapy with the new biological DMARD. However, although reports on cohorts are useful to generate hypotheses, only well-conducted randomized prospective clinical trials can provide definitive answers. In diabetes mellitus, another disease in which cardiac complications are important, the new randomized clinical trials of oral hypoglycemic agents are not only focusing on lowering HbA1c, but on prevention of cardiovascular events. This approach has resulted in important discoveries leading to use of these drugs in nondiabetic patients at high cardiovascular risk.20McMurray J.J.V. Solomon S.D. Inzucchi S.E. et al.DAPA-HF Trial Committees and InvestigatorDapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med. 2019; 381: 1995-2008Crossref PubMed Scopus (1418) Google Scholar Having prespecified cardiac endpoints in future randomized trials of inflammatory rheumatologic diseases, may similarly contribute to the identification of new drugs that may be beneficial in patients without overt inflammation but at high cardiovascular risk.