Up to 1% of the global population suffers from rheumatoid arthritis (RA), which is the most prevalent form of inflammatory arthritis in the world.1 In addition to the hallmark joint-related symptoms, cardiovascular disease (CVD) is substantially higher in patients with RA: their risk of both coronary artery disease (CAD) and heart failure is up to twice that of the general population. This elevated risk has prompted the European League Against Rheumatism to suggest that clinicians multiply Framingham CV risk scores by 1.5 for certain patients with RA.2
The cause of the RA-CVD link is unclear, although viral infection has been implicated in some studies.3 The authors of a new review published in Circulation Research make the case that cytomegalovirus (CMV) is a major driver of CVD in RA.4
- Future studies should stratify patients with rheumatoid arthritis, and patients with cardiovascular disease in general, by cytomegalovirus status.
Coauthor Florian Kern, PhD, chair of immunology and deputy director of research at Brighton and Sussex Medical School in the United Kingdom, elaborated on their conclusions in an interview with Rheumatology Advisor.
Rheumatology Advisor: What are some of the most compelling areas of evidence pointing to CMV as the major contributor to CVD in RA?
Dr Kern: The most compelling evidence is related to a white blood cell subset referred to as CD4+CD28- T lymphocytes. The presence and size of this subset appear to correlate with the presence and/or severity of CV complications in RA patients. We also know that these cells can directly cause vascular damage and, unless CMV infection is present, they will not expand beyond very small numbers.
So, clearly these expansions are triggered by CMV infection. We do not fully understand how this happens, but we know that many of these cells recognize CMV. Their expansion may be triggered as a result of changes that occur in response to CMV infection or because of antigen cross-reactivity. It is important to understand that most existing reports on CD4+CD28- T lymphocytes in RA patients with CVD did not look at the CMV infection status of the studied individuals. However, we now understand that expansions of these cells beyond very small numbers are limited to the CMV-infected population of RA patients.
Rheumatology Advisor: What are your thoughts on why that link has not previously been considered?
Dr Kern: I am sure that researchers have thought about this link in the past. However, there has been a plethora of publications linking CMV to a host of problems in recent years and this might, in a way, have undermined the credibility of these links. A lot of reported associations are indirect and may ultimately be explained by epidemiological associations between CMV infection and many of the conditions and circumstances that are associated with heart disease, such as low socioeconomic status, smoking, unhealthy diets, or elevated cholesterol levels. However, here we have a direct, mechanistic link: a T-cell subset that is directly involved in causing damage to blood vessels and the expansion of which is driven by CMV infection.
There has clearly been a lack of awareness. That CMV infection is the major driver of the expansions of CD4+CD28- T cells in RA patients has simply not been recognized widely enough. It would have been very cheap to add CMV serology to many of the published studies, and this would have clarified the situation. I am very grateful to those researchers who have looked at CMV infection status in this situation. This has made a tremendous difference. We have recently studied almost 200 older people with respect to CD4+CD28- T cells and CMV infection status, and this has confirmed that expansions of CD4+CD28- T cells are indeed limited to CMV-infected participants. These results will be published later this year.
Rheumatology Advisor: What are some of the mechanisms by which CMV is believed to drive this risk?
Dr Kern: I believe the most prominent mechanism is that CMV induces cytotoxic CD4+CD28- T cells to expand and these cells directly attack vascular tissue. Some CD8 T-cell subsets might also be directly involved in this process. Vascular tissue is, interestingly, a prime target of CMV infection.
In addition, we also know from published research that T cells are an important factor in the pathogenesis of hypertension; these associations began to emerge a while ago. Hypertension is obviously a risk factor for CVD. Also, researchers have been able to show that experimental CMV infection can cause hypertension in mouse models.
Rheumatology Advisor: How does this fit with the apparent link between other types of infection and RA?
Dr Kern: An infectious cause of RA has been discussed for a very long time. There are many interesting leads but ultimately no conclusive ones. It may well be that a range of organisms is directly or indirectly involved in the pathogenesis of RA and possibly not the same organisms in everyone. CMV is present in a large percentage of the population, independently of other infections. However, there is no conclusive evidence that it causes or is involved in causing RA.
Rheumatology Advisor: What are the potential treatment implications of these findings?
Dr Kern: This really is the next step. Ideally a preventive treatment in CMV-infected people would stop or slow down the process that leads to CVD complications. Existing anti-CMV drugs have many adverse effects, and it is unclear if they could reverse the problem if administered to people with expansions of CD4+CD28- T cells, for example. Researchers are indeed already looking at ways to target these cells in other contexts. I think treatment options might become clearer once we understand the actual disease process a little bit better.
Rheumatology Advisor: What should be the next steps in terms of research in this area?
Dr Kern: I think the most important and immediate next step should be to stratify RA patients and patients with CVD, in general, by CMV status. The cost of such a test is very low, but it would massively increase our awareness and might highlight the extent of the problem. I believe that if a sufficiently large number of researchers and physicians push for it, funds may become available to develop new drugs to address the problem of chronic CMV infection with its associated immune pathology rather than just acute CMV disease. Our analysis in RA patients might just have revealed the tip of the iceberg.
- Rheumatoid arthritis facts and statistics. Orlando, FL; RheumatoidArthritis.org. Available at: https://www.rheumatoidarthritis.org/ra/facts-and-statistics. Accessed February 24, 2017.
- Crowson CS, Liao KP, Davis JM, et al. Rheumatoid arthritis and cardiovascular disease. Am Heart J. 2013;166(4):622-628.e1. doi: 10.1016/j.ahj.2013.07.01
- Halenius A, Hengel H. Human cytomegalovirus and autoimmune disease [published online April 29, 2014]. Biomed Res Int. 2014;2014:472978. doi:10.1155/2014/472978
- Pera A, Broadley I, Davies KA, Kern F. Cytomegalovirus as a driver of excess cardiovascular mortality in rheumatoid arthritis: a red herring or a smoking gun? Circ Res. 2017;120(2):274-277. doi:10.1161/CIRCRESAHA.116.309982