Interdependent Cardiometabolic and Psoriatic Disease: An Intriguing Process That Calls for Far More Integrative Intervention

Psoriatic disease (PsD) comprises psoriasis (PsO) and psoriatic arthritis (PsA), which are chronic immune-mediated inflammatory diseases (IMIDs).¹ In mostly high-income White populations, the prevalence of PsO is 2% to 3% and that of PsA 0.1% to 1%. The prevalence of PsD is reportedly somewhat lower in low-income populations, including in Asian and African people.² In 85% of patients with PsA, musculoskeletal involvement develops after the onset of PsO. PsD causes substantial morbidity and excess mortality. Increased cardiovascular (CV) event rates that are mediated by both systemic inflammation and traditional CV risk factors account for most of the excess mortality in PsD.¹

Until recently, recommended pharmacological interventions for PsD control included nonsteroidal antiinflammatory agents; local glucocorticoid infiltrations; and methotrexate, sulfasalazine, and leflunomide as conventional synthetic disease-modifying antirheumatic drugs (DMARDs).³ However, the past 3 decades have witnessed major breakthroughs in the elucidation of the PsD pathophysiology. In this regard, interleukin (IL)-12 and its related IL-23, IL-17, and tumor necrosis factor (TNF) were identified as pivotal cytokines and create a self-perpetuating inflammatory loop in PsD.⁴ With the intense involvement of the pharmaceutical industry, this was soon followed by the introduction of a wide range of biologic agents that targeted the respective molecules and were proven to be often highly effective in controlling PsD.³ More recently, targeted synthetic (ts-) DMARDs in the form of Janus kinase inhibitors were added to the armamentarium that can control PsD activity.³

Contemporary to the disentanglement of the cytokine network in both PsO and PsA, the potential involvement of cardiometabolic risk factors in PsD pathophysiology has drawn increasingly more attention by investigators over the recent past.^1,5 Notably, chronic IMIDs are by themselves recognized to increase cardiometabolic risk through high-grade inflammation.¹ This phenomenon was most consistently documented in rheumatoid arthritis (RA). Indeed, in RA, high-grade inflammation affects body composition with increased fat mass and loss of lean mass, and associates with insulin resistance, diabetes prevalence, mostly adverse changes in lipoprotein levels and function, as well as in blood pressure. These changes can be reversed with adequate RA control. However, a striking finding among chronic IMIDs is that PsD is far more strongly and consistently associated with cardiometabolic risk when compared to other chronic IMIDs.¹ Moreover, and importantly in the present context, systemic inflammation does not fully account for insulin resistance and other metabolic risk factors in PsD.¹

Excess adiposity and related insulin resistance are the core mechanisms in the metabolic syndrome that comprises a cluster of CV risk factors including impaired glucose metabolism, dyslipidemia, and hypertension.¹ Excess adiposity in otherwise healthy persons is associated with an increased incidence of PsD in a dose-dependent manner.^1,5 Also, insulin sensitivity associates inversely with PsA severity. Patients with PsD further experience an increased frequency of metabolic dysfunction–associated steatotic liver disease, formerly nonalcoholic fatty liver disease, which is the hepatic component of metabolic syndrome and associates with increased CV risk. Yet, these data originate in observational clinical and epidemiological studies, which, unlike randomized controlled trials, cannot determine disease mechanisms with certainty due to the possibility of residual confounding and reverse causality. It is in this context that the introduction of Mendelian randomization (MR) studies during the past decade has shown promise in enhancing our understanding of the pathophysiology of PsD and its associated increased risk of CV disease.^6-14

MR studies employ genetic variants that are strongly associated with the exposure variable of interest.⁶ These genetic variants are then used as an instrumental variable and proxy for the exposure. Genetic variants are randomly allocated from parents to the offspring during gamete formation at conception. Hence, by using genetic variants as instrumental variables, confounding and reverse causation are avoided. In other words, although MR is performed under certain assumptions, it is considered a reliable method in the identification of causal relationships. MR can assist in identifying and prioritizing drug targets to inform clinical trials.

In 2019, Budu-Aggrey and colleagues⁷ reported an MR analysis that revealed genetically predicted BMI was associated with PsO. In a reverse MR analysis performed in the same study, genetic liability for PsO was not associated with BMI. Several subsequent MR analyses confirmed the causal relationship of BMI with PsD, including in patients with PsA.⁸ The Figure illustrates results of reported MR analyses that aimed to identify causal relationships among PsD and a wide range of cardiometabolic risk factors and diseases.^7-14 Besides genetically predicted adiposity as assessed by BMI, genetically predicted/genetic liability to favorable (metabolically healthy) as well as unfavorable (metabolically unhealthy) adiposity,⁹ childhood and adult body size,⁸ glucose metabolism variables including type 2 diabetes mellitus and glycated hemoglobin and blood sugar levels,^8,10 lipid variables comprising familial hypercholesterolemia,¹¹ remnant cholesterol concentrations (increased in metabolic syndrome and calculated by subtracting low-density lipoprotein [LDL] cholesterol and high-density lipoprotein cholesterol from total cholesterol concentrations)¹² and low proprotein convertase subtilisin/kexin type 9 inhibition,¹³ and levels of inflammatory markers encompassing IL-17, C-reactive protein, and IL-12B⁸ were all causally associated with PsD. Conversely, genetic liability to PsD is causally associated with lipid variables that include LDL cholesterol, apolipoprotein B, and lipoprotein(a) levels¹⁴ and, importantly, CV diseases comprising coronary artery disease, stroke, heart failure, and atrial fibrillation.^8,10 Moreover, LDL cholesterol, apolipoprotein B, and lipoprotein(a) concentrations were found to mediate 4.1% to 10.2% of the effect of PsD on myocardial infarction risk.¹⁴ Taken together, recently reported MR findings provide ample and consistent evidence that cardiometabolic risk factors contribute to PsD and that PsD increases atherogenic lipids as well as the risk of CV disease.^7-14 The therapeutic implications of these findings are substantial in that they indicate that adequate management of excess adiposity and its related metabolic abnormalities can be expected to reduce PsD incidence and severity, whereas optimal PsD control can reduce CV event rates, partially through improving lipid metabolism. Overall, MR analyses have shown that cardiometabolic disease and PsD are highly interdependent.

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Figure.

Causal relationships among psoriatic disease and cardiometabolic risk factors and disease as identified in Mendelian randomization studies. The arrows show the direction of causality. AF: atrial fibrillation; CAD: coronary artery disease; HbA1C: glycated hemoglobin. HF: heart failure; LDL: low-density lipoprotein; PCSK9: proprotein convertase subtilisin/kexin type 9; PsA: psoriatic arthritis; PsD: psoriatic disease; PsO: psoriasis.

Future mechanistic studies are needed to explain how obesity and related cardiometabolic risk factors affect PsD. Meanwhile, in PsD, the inflammatory cascade comprises activated dendritic cells and macrophages that produce IL-23, which then in turn triggers activation of other immune cells to produce IL-17 and, in the end, TNF.⁴ A remarkably similar process occurs in adipose tissue among persons with particularly visceral obesity, which leads to overproduction and consequently increased circulating levels of the same cytokines as those encountered in PsD.¹⁵ It therefore appears feasible, if not likely, that together with obesity-induced proinflammatory adipokine profiles, excess visceral fat–derived cytokines can trigger and enhance PsD in genetically predisposed individuals. Of note in this context, as applies to PsD, obesity is a highly heritable and hence genetically mediated disease.

Very recently, Siebert and colleagues⁵ elegantly reviewed the evidence derived from clinical studies that supports the role of excess adiposity in PsD. As alluded to above, adiposity increases PsD incidence in a dose-dependent manner. A long-term nationwide Danish study found that gastric bypass surgery reduced the incidence of PsO, progression to severe PsO, and progression to PsA significantly by 48%, 56%, and 71%, respectively. During a 4-month period, a very low energy diet in PsA patients with obesity on antirheumatic agents resulted in 18.7-kg weight loss and increased the percentage of patients with minimal disease activity from 29% to 54% in a dose-dependent response manner. Among patients with PsA and overweight or obesity in whom TNF inhibition was initiated together with either a hypocaloric diet or free-managed diet for 6 months, > 10% weight loss increased the minimal disease activity achievement rates 6.7-fold, irrespective of the applied dietary intervention.

Examples of recommended weight-reducing dietary interventions include strict calorie restriction, time restriction (intermittent fasting; eg, Ramadan), and food type restriction (eg, avoidance of proinflammatory foods, such as in the Mediterranean diet and ketogenic diet).^1,5,16-18 Notably, time and food type restriction result indirectly in lower calorie intake and may be perceived as more sustainable. Ultimately, calorie restriction is likely the most important target in the present context. The use of each of these approaches was recently reported on in short-term investigations among patients with PsA, with variable beneficial effects on cardiometabolic risk, disease activity, and circulating inflammatory markers.^1,5,16-18

Both PsD and obesity are not only highly genetically mediated but also chronic diseases. In this regard, short-term intervention through calorie restriction is reportedly effective in persons with excess adiposity, including those with PsD.^5,16-18 By contrast, the reality and major challenge in the context of obesity is that long-term and optimal sustained weight loss through calorie restriction remains characteristically unattainable.^5,19 As also timely dealt with by Siebert and colleagues,⁵ the introduction of the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide and dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonist tirzepatide requires urgent consideration in the management of PsD patients with concomitant excess adiposity. These agents were shown to cause a 15% and 20% weight loss that is sustained over 3 and 4 years, respectively. In a randomized controlled trial, liraglutide decreased IL-23, IL-17, and TNF expression in the skin of patients with PsO with concomitant diabetes and obesity. A randomized controlled trial of the IL-17A inhibitor ixekizumab vs combination therapy ixekizumab and tirzepatide among patients with PsA and obesity has been initiated.

As excess adiposity can attenuate the efficacy of TNF inhibitors in PsD,⁵ the question arises as to whether cardiometabolic risk profiles should be considered upon selecting biologic DMARDs in individual patients. Interestingly, whereas obesity may impair the therapeutic response to the IL-17A inhibitor secukinumab in patients with PsO, this does not appear to be the case in those with PsA.²⁰ Conversely, data on whether biologic agents as currently recommended in PsD have a differential effect on CV outcomes remain sparse. In this regard, upon employing the TriNetX database, Geiger and colleagues²¹ identified 32,758 patients with PsD that were new biologic DMARD users and were followed for an average of 3.34 (SD 2.46) years, in this issue of The Journal of Rheumatology.²¹ Such investigations are of utmost importance as clinical trials are primarily designed to show efficacy, with the aim of obtaining approval for use from government agencies, and are often underpowered to assess infrequent yet serious adverse events. Using appropriate data analyses, Geiger and colleagues found no differences in major adverse cardiac events among TNF, IL-17A, IL-23, or IL-12/23 inhibitor users.²¹ Despite the observational nature of this study, the findings are reassuring and indicate that CV risk may not need to be considered upon selecting biologic DMARDs for use in PsD.

Besides adequate weight control, physical activity likely needs to be consistently addressed in the management of PsD and its associated cardiometabolic risk.¹ In this regard, a recent investigation reported markedly impaired cardiorespiratory fitness in patients with PsA that was associated with not only low physical activity levels but also reduced disease control and increased cardiometabolic risk.²² Whereas much more research is needed to address this issue,²³ regular physical activity can further assist in obtaining particularly sustained weight control in a dose-response manner.^24,25

In conclusion, ample evidence has been reported over the recent past that cardiometabolic risk factors/disease and PsD are strongly and consistently interdependent. This calls for far more integrated intervention than is currently practiced. In this regard, besides assessing PsD activity and prescribing antirheumatic agents, personalized evaluation and management of cardiometabolic risk factors and its determining lifestyle factors, including weight control and enhanced physical activity, should be consistently performed from the intervention outset and over time. Perhaps, at this stage and this time around, we should no longer wait for the pharmaceutical industry to further delineate the role of weight-loss drugs in patients with PsD. A multidisciplinary approach is desirable in this context but often difficult to implement due to availability, cost, and time constraints. Meanwhile, nothing prohibits dermatologists and rheumatologists from actively guiding patients with PsD in comprehensively managing their cardiometabolic risk.

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