Metabolic syndrome, rheumatoid and psoriatic arthritis: Managing cardiovascular risk

Abstract

There is an increased risk of cardiovascular disease (CVD) and mortality in people with rheumatoid arthritis (RA) and psoriatic arthritis (PsA).1-4 There have been improvements in disease-specific rheumatological outcomes in these conditions, aided by earlier recognition, tighter control approaches and more effective treatments. The focus is now shifting to concurrently preventing and managing co-morbidities, with some international rheumatology and dermatology guidelines now incorporating advice on co-morbidity management.5-8 However, it remains uncertain if the increased CVD risk is simply due to an increased clustering of established risk factors, or whether people with RA and PsA have a higher intrinsic risk of CVD. Metabolic syndrome (MetS) is one such established CVD risk factor. It is defined as a cluster of 3 out of 5 risk factors including central obesity, hyperglycemia, raised triglyceride levels, reduced high-density lipoprotein (HDL) levels or hypertension.9, 10 Both central obesity/adiposity and MetS are linked to chronic inflammation and insulin resistance,11, 12 with inflammation also being linked to CVD risk.13, 14 According to the World Health Organization, the worldwide prevalence of obesity in adults has tripled since 1975, and in 2016 the prevalence of overweight and obesity was 39% and 13% respectively.15 The prevalence does vary significantly by country or region, and in the USA, the obesity prevalence in adults was much higher at 42.4%.16 With the increasing prevalence of obesity, the prevalence of MetS has also been increasing over time in the USA from 25.3% in 1988-1994 to 34.2% in 2007-2012.17 A systematic review by Loganathan et al.18 in this issue of the Journal has clearly demonstrated a higher prevalence of MetS in patients with PsA (46%) compared to psoriasis (31%). The higher disease activity and inflammation in PsA compared to psoriasis may explain this difference in prevalence. Interestingly, in this study, the prevalence of MetS in RA is significantly lower (34%) than PsA, and is comparable to psoriasis. In another hospital-based study from Eastern China by Kong et al.,19 also published in this issue of this Journal, the prevalence of MetS in RA was actually very similar to healthy comparators, 31% vs 34%, and similar to the prevalence in the systematic review. These findings do raise some questions, given that RA is clearly an inflammatory condition, and as previously mentioned, is associated with a higher CVD risk. A higher prevalence of MetS in PsA may potentially account for a higher CVD risk, although other factors could still be at play. However, there certainly seem to be factors beyond the traditional risk factors and MetS that drive the higher CVD risk in RA. The European League Against Rheumatism (EULAR) guidelines recommend early and aggressive screening and management of traditional CVD risk factors and components of MetS for all inflammatory joint disorders including PsA and RA.5 While CVD risk management is a sensible first step in high-risk populations, the strength of these recommendations are moderate to low in PsA or RA. There is a lack of good-quality evidence that this risk management actually results in reduced CVD events or death in PsA or RA. The limited use of nonsteroidal anti-inflammatory drugs and corticosteroids is also suggested due to the potential of increased CVD risk and/or worsening of hypertension/hyperglycemia. Given that the prevalence of CVD in RA is significantly higher than the general population, the current studies support these EULAR guidelines that also suggest that CVD risk prediction models should be adapted for patients with RA by a 1.5 multiplication factor. Another factor to consider is that the presence of MetS is often considered as binary – present or absent, based on whether 3 of 5 of the criteria are met.9, 10 However, age or gender may have a role in the significance of the presence of MetS, as may clustering of the individual components of MetS.20 For example, a person with 0 or 2 risk factors would be considered to have no MetS, while a person with 3, 4 or 5 risk factors would all be considered to have MetS, with actual risk of CVD being on a spectrum. Findings from the study by Kong et al.19 showed that although the prevalence of MetS in those with and without RA was similar, there was a greater prevalence of hypertension and low HDL levels in the RA patients, and they also had lower body mass indexes and triglyceride levels compared to patients without RA. Regular screening for MetS components as well as lifestyle advice on smoking cessation, healthy eating and increased physical activity where practical, should be offered to all patients. This may be with the rheumatologist or general practitioner or other healthcare professional, depending on the healthcare setting. The arrival of statins was a major game changer when it came to reducing CVD risk, but the arrival of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has the potential to take lipid lowering to the next level.21 And in people with type 2 diabetes mellitus (T2DM), the evidence that sodium glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP1) agonists help with weight loss and improved glycemia, and also independently reduce cardiovascular risk makes them an attractive therapeutic option.22 These new medications are not without cost implications, and some of these may require the involvement of healthcare providers other than rheumatologists. Given that central obesity and adiposity are integrally linked to inflammation and insulin resistance in MetS, significant weight loss may be an option to reduce CVD risk. In addition to the metabolic improvements, weight loss could also reduce the mechanical load on joints. However, there is ample evidence that just asking people to improve lifestyle and attempt to lose weight does not work, and specific targeted interventions with appropriate support are more likely to result in change. This may be in the form of intensive lifestyle interventions, low energy diets, pharmacotherapy or bariatric surgery. While low or very low energy diets can result in significant weight loss, they are not always sustained, whereas bariatric surgery is often linked to significant and sustained weight loss and improvement in glycemia. Current pharmacotherapy results in modest weight loss but new and emerging therapies have been shown to result in significant weight loss of around 15% body weight, that is sustained with once a week subcutaneous injections.23, 24 These options, along with the increasing availability of bariatric surgery present significant weight loss as an achievable option for many people with RA or PsA. However, data from the prospective Swedish Obesity Study on patients without RA or PsA at baseline showed a reduced risk of developing psoriasis in those who had bariatric surgery compared to controls but no difference in development of PsA or RA during follow-up.25, 26 The total number of people developing these conditions was very low in this study though, despite up to 26 years follow-up data. There are a few studies of bariatric surgery in people with pre-existing psoriasis or PsA27-29 or RA,30, 31 but the results of these studies are mixed with no clear benefit in RA or PsA following bariatric surgery. Moreover, the number of patients were quite small, and the follow-up duration limited. The other question that remains is whether treatments targeting inflammation itself which improve inflammatory arthritis, also influence inflammation linked to obesity, MetS and CVD. There is limited evidence of the effect of the newer biological therapies on CVD risk. Previous attempts to treat inflammation have had mixed results with some suggestion that methotrexate reduces CVD risk in RA, and tumor necrosis factor inhibitors reduce CVD risk in psoriasis/PsA as well as RA.32, 33 Results from the trial on the monoclonal antibody targeting interleukin-1b, canakinumab, showed reduced CV events with 150 mg dose but not 50 mg or 300 mg, and it had a higher risk of fatal infection compared to placebo.34 In summary, while chronic inflammation may link PsA and RA with an increased CVD risk, the prevalence of MetS alone may not account for this, particularly in RA where the prevalence of MetS was comparable to the background population. Attention may need to be paid to the individual components of MetS as well as the influence of age and gender when considering CVD risk. Early screening for and aggressive management of traditional CVD risk factors including the components of MetS are recommended. However, good-quality long-term studies are needed to demonstrate if managing risk factors brings CVD risk down to the level of the background population. Newer therapeutic options may help achieve these goals, particularly with the availability of PCSK9 inhibitors for lipid lowering, and of SGLT2 inhibitors and GLP1 agonists for glycemic control in T2DM. And although options for significant weight loss are available, including bariatric surgery and newer pharmacological options, further studies are required to determine if this weight loss results in improvement in disease activity in inflammatory arthritis. The use of anti-inflammatory therapies for the reduction of CVD risk may not be recommended at the moment, due to the prohibitive cost and risk of side effects, but they may influence the decision to start biological therapies in patients with RA or PsA if they have a higher CVD risk. With existing and emerging therapies to help reduce inflammation and manage CVD risk factors, rheumatologists need to be prepared for the increasingly expanding role beyond simply managing the inflammatory joint disease itself.

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