Introduction
During the twenty-first century, psoriatic diseases and their associated comorbidities have become an active area of investigation. Psoriatic diseases typically refer to psoriasis and psoriatic arthritis. Psoriasis is a common, chronic inflammatory disease that affects 3.2 % of US adults, totaling an estimated 7.4 million people [1]. Globally, the prevalence of psoriasis is higher in adults than in children and varies based on geographic location, ranging from 0 % in Latin America to 2.9 % in Denmark for all ages [2]. Overall, psoriasis is more common in regions located farther from the equator, such as Europe and Australia, than in those closer to the equator, such as Tanzania, Sri Lanka, and Taiwan [2]. Psoriasis is associated with a significantly increased risk of certain comorbid diseases; some studies have shown a dose–response relationship between psoriasis disease severity and incidence of selected comorbidities [3]. Patients with psoriasis have increased prevalence of pulmonary, hepatic, renal, cardiovascular, and rheumatologic illnesses [3]. In particular, a preponderance of the literature suggests that psoriasis and psoriatic arthritis confer an independent risk of cardiovascular disease and death [4‐7]. Specifically, patients with psoriasis and/or psoriatic arthritis are at an increased risk of myocardial infarction, stroke, and cardiovascular mortality [4‐7]. Notably, cardiovascular disease is the most common cause of death among patients with severe psoriasis [8]. Because of its high clinical impact and critical implications, active research is ongoing to elucidate the relationship and shared pathogenic mechanisms between psoriatic diseases and cardiovascular diseases. In this review, we will focus on discussing (1) the epidemiologic association between psoriasis and cardiovascular risk factors, (2) the epidemiologic association between psoriasis and major adverse cardiovascular events (MACE), (3) the epidemiologic association between psoriatic arthritis, cardiovascular risk factors, and MACE, and (4) proposed mechanisms for the contribution of psoriatic diseases to cardiovascular diseases. How systemic therapeutics for psoriatic diseases may affect cardiovascular comorbidities is beyond the scope of this paper. This manuscript does not purport to perform an exhaustive accounting of all studies published in this area; rather, it highlights several representative studies that reflect the overall rigorous, concerted effort by the scientific community to determine the relationship between psoriatic diseases and cardiovascular comorbidities.
In this review, we used the following search guidelines to identify the relevant articles. We searched relevant literature from PubMed in the subject areas of psoriasis, psoriatic arthritis, cardiovascular risk factors, cardiovascular comorbidities, and mechanisms of psoriatic disease and cardiovascular comorbidities in the past 10 years, specifically January 2006–December 2015. We reviewed the available abstracts and selected literature that met the following criteria: (1) primary article, systematic review, or meta-analysis, (2) investigated the relationship between psoriasis, cardiovascular risk factors, and MACE, (3) investigated the relationship between psoriatic arthritis, cardiovascular risk factors, and MACE, and (4) investigated the mechanisms linking psoriatic diseases to cardiovascular diseases. We excluded case reports and case series because of their lack of systematic collection of data.
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Epidemiologic association of psoriasis and cardiovascular risk factors
Psoriasis is associated with multiple cardiometabolic diseases, which are divided into cardiovascular risk factors and MACE. The strength of the association between psoriasis and cardiometabolic diseases is often dependent on psoriasis disease severity. For example, those with more severe psoriasis tend to be at greater risk of cardiometabolic diseases. It is important to note that classification of psoriasis disease severity is not entirely clear-cut. Multiple ways of defining psoriasis disease severity have been proposed, and one definition that is widely accepted is the definition created by the National Psoriasis Foundation. In this particular classification, mild psoriasis is defined as less than 3 % body surface area (BSA) involvement; moderate psoriasis is defined as 3–10 % BSA involvement; and severe psoriasis is defined as greater than 10 % BSA involvement [9].
Specifically, psoriasis is associated with cardiovascular risk factors including obesity, hypertension, diabetes, dyslipidemia, and metabolic syndrome, all of which contribute to an increased risk of cardiovascular morbidity and mortality. First, the risk of obesity increases with psoriasis severity, with an odds ratio (OR) of 1.27 (95 % CI 1.24–1.31) among patients with mild psoriasis and 1.79 (95 % CI 1.55–2.05) among patients with severe psoriasis [10]. The prevalence of obesity in patients with mild and severe psoriasis is also 15.8 and 20.7 %, respectively, compared to 13.2 % in the control population. This is after adjusting for age, gender, person-years, and all cardiovascular risk factors.
Second, patients with psoriasis have a severity-dependent risk of uncontrolled hypertension [11] and increased difficulty in controlling their hypertensive state [12]. The adjusted OR of uncontrolled hypertension in patients with severe psoriasis is 1.48 (95 % CI 1.08–2.04) [11]. Hypertensive patients with psoriasis are also increasingly more likely to be on multiple antihypertensive therapies than hypertensive patients without psoriasis [12].
Third, psoriasis is associated with diabetes mellitus, another major cardiovascular risk factor. According to a Danish study of diabetes in psoriasis patients, all severities of psoriasis confer significantly higher new-onset diabetes incidence rates [13]. The incidence rates for the control population, mild psoriasis, and severe psoriasis are 3.67 (95 % CI 3.65–3.69), 6.93 (95 % CI 6.63–7.25), and 9.65 (95 % CI 8.68–10.73), respectively.
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Fourth, dyslipidemia is a major contributor to cardiovascular morbidity and mortality that may also be associated with psoriasis. While some studies show that patients with psoriasis have significant dyslipidemia [14‐18], other studies do not [19‐22]. This association may be less well defined due to different definitions of dyslipidemia, which could include hyperlipidemia, hyperlipoproteinemia, reduced HCL-cholesterol, or hypertriglyceridemia. Even the value ranges for the same designation of dyslipidemia, for example, hypertriglyceridemia, may be different among studies. Importantly, as research emerges regarding impaired function of lipids among psoriasis patients, we are increasingly cognizant of the observation that, aside from the plasma lipid levels, the function of lipids may be central to elucidating the link between psoriasis and dyslipidemia.
Last, psoriasis is strongly associated with metabolic syndrome. Metabolic syndrome, as defined by the National Cholesterol Education Program Adult Treatment Panel III, is the presence of three or more of the following: increased obesity, hypertriglyceridemia, decreased HDL cholesterol, hypertension, and increased fasting blood glucose [14]. Metabolic syndrome has a severity-dependent association with psoriasis, with a prevalence of 40 % in patients with psoriasis compared to a prevalence of 23 % in patients without psoriasis [14, 15]. In addition, 58.6 % of patients with moderate-to-severe psoriasis have 2 or more cardiovascular risk factors and 28.8 % have 3 or more [16].
Epidemiologic association between psoriasis and major adverse cardiovascular events (MACE)
Patients with psoriasis also have an increased risk of MACE, namely myocardial infarction, stroke, and cardiovascular death [4‐7]. This association remains after adjusting for the various cardiovascular risk factors, including hypertension, diabetes, hyperlipidemia, age, sex, smoking, and body mass index, which indicates that psoriasis poses an independent risk of cardiovascular disease. A Danish nationwide study confirmed these results [23]. In patients with mild and severe psoriasis, the rate ratios were 1.22 (95 % CI 1.12–1.33) and 1.45 (95 % CI 1.10–1.90) for myocardial infarction, 1.25 (95 % CI 1.16–1.33) and 1.71 (95 % CI 1.39–2.11) for stroke, and 1.14 (95 % CI 1.06–1.22) and 1.57 (95 % CI 1.27–1.94) for cardiovascular death, respectively. In addition, patients with psoriasis have a higher prevalence of coronary artery disease [24, 25] and worse prognoses after myocardial infarction than patients without psoriasis [26]. Congruently, subsequent studies have shown that severe psoriasis confers an increased 10-year risk, specifically an additional 6.2 % absolute risk, of myocardial infarction, stroke, or cardiovascular mortality [16, 27]. Psoriasis significantly increases the risk of composite cardiovascular outcome, defined by first incidence of myocardial infarction, stroke, or cardiovascular death [28]. This risk persists after adjusting for traditional cardiovascular risk factors and is elevated in patients not taking disease-modifying antirheumatic drugs (DMARD) (HR 1.08; 95 % CI 1.02–1.15), as well as in patients taking DMARD (HR 1.42; 95 % CI 1.17–1.73).
However, other studies have shown that psoriasis is not an independent risk factor for adverse cardiovascular outcomes. These studies typically have found that there are other factors that confound or are more contributory to cardiovascular comorbidities, namely relevant cardiovascular risk factors [29]. One study showed that while psoriasis confers a significantly increased risk of MACE after adjusting for age and gender, (HR 1.10; 95 % CI 1.04–1.17), this risk is diminished after adjusting for known cardiovascular risk factors (HR 1.02; 95 % CI 0.95–1.08). The inconsistency in these findings for or against psoriasis being an independent risk factor for adverse cardiovascular outcomes can be attributed to a number of factors: (1) Study populations are different, which results in variation in whether psoriasis poses an independent cardiovascular risk, (2) definitions of outcomes and how these outcomes are classified may differ even within the same study population, and (3) statistical modeling among individual studies can be different, including the identification of confounders and mediating factors. This underscores the need for more rigorous examinations of population-level data using comprehensive identification of confounders, in the absence of available randomized controlled trials.
Summary of epidemiologic results on the association between psoriasis, cardiovascular risk factors, and MACE
Numerous studies have been conducted to analyze the association between psoriasis and cardiovascular risk factors or MACE. Table 1 provides a summary of the results of studies analyzing the association of psoriasis, mild psoriasis, and severe psoriasis with cardiovascular risk factors. All of these studies are meta-analyses, with the exception of where results from meta-analyses are not available for certain comparisons [14, 30‐33]. For example, Langan et al. were used to characterize the dose–response relationship of psoriasis and metabolic syndrome. Table 2 provides a summary of the results from two meta-analyses analyzing the association of mild psoriasis and/or severe psoriasis with MACE [7, 34]. Samarasekera et al. found that only severe psoriasis confers an increased risk of MACE, which is summarized in table.
Table 1
Odds ratios (95 % CI) for cardiovascular risk factors for patients with psoriasis, mild psoriasis, and severe psoriasis compared to the general population
Cardiovascular risk factors | Psoriasis | Mild psoriasis | Moderate-to-severe psoriasis | Relevant references |
---|---|---|---|---|
Obesitya
| 1.66 (1.46–1.89) | 1.46 (1.17–1.82) | 2.23 (1.63–3.05) | [30] |
Hypertensiona
| 1.58 (1.42–1.76) | 1.30 (1.15–1.47) | 1.49 (1.20–1.86) | [31] |
Type 2 diabetes mellitusa
| 1.59 (1.38–1.83) | 1.53 (1.16–2.04) | 1.97 (1.48–2.62) | [32] |
Metabolic syndrome | 2.26 (1.70–3.01)a
| 1.22 (1.11–1.35)b
| 1.98 (1.62–2.43)b
|
Table 2
Risk ratios (95 % CI) of MACE for patients with mild psoriasis and severe psoriasis compared to the general population
MACE | Mild psoriasis | Moderate-to-severe psoriasis | Relevant references | |
---|---|---|---|---|
Myocardial infarction | 1.29 (1.02–1.63)a
| 1.70 (1.32–2.18)a
| 3.04 (0.65–14.35)b
| |
Stroke | 1.12 (1.08–1.16)a
| 1.56 (1.32–1.84)a
| 1.59 (1.34–1.89)b
| |
Cardiovascular mortality | 1.03 (0.86–1.25)a
| 1.39 (1.11–1.74)a
| 1.37 (1.17–1.60)b
|
Epidemiologic association of psoriatic arthritis, cardiovascular risk factors, and MACE
Psoriatic arthritis (PsA) is an inflammatory disease of the joints characterized by joint damage, skin lesions, and disability [35]. PsA occurs in approximately 30 % of psoriasis patients, and its risk increases with psoriasis severity [35, 36]. Like psoriasis, PsA is associated with cardiovascular risk factors and MACE. Specifically, PsA has linked to obesity, hypertension, diabetes, and dyslipidemia, which contribute to an increased risk of MACE [37‐39]. Among PsA patients, 55 % had hypertension, 32 % had dyslipidemia, 29 % had hypertriglyceridemia, and 23 % had diabetes [37]. With regard to the relationship between PsA and MACE, PsA is directly related to composite myocardial infarction, stroke, or cardiovascular death with a rate ratio of 1.79 (95 % CI 1.31–2.45) [23]. Another study has shown that PsA confers a fully adjusted composite cardiovascular risk among PsA patients not taking DMARD (HR 1.24; 95 % CI 1.03–1.49), as well as among PsA patients taking DMARD (HR 1.17; 95 % CI 0.95–1.46) [28]. While more extensive studies are necessary to refine the risks associated with PsA, these data suggest that PsA poses an independent risk of cardiovascular risk factors and MACE. Some researchers even suggest that the association of PsA with cardiovascular risk factors and MACE may be stronger than that in psoriasis [40, 41].
Proposed mechanisms for the contribution of psoriatic diseases to cardiovascular diseases
While there has been significant headway in the epidemiology of psoriatic and cardiovascular diseases, the understanding of shared mechanisms is still lacking. A number of contributions linking psoriatic and cardiovascular diseases have been identified and will be discussed in this review, including inflammation, insulin resistance, dyslipidemia, angiogenesis, oxidative stress, and endothelial dysfunction. However, it is important to recognize that there is significant overlap and interplay among these mechanistic pathways. For example, inflammation is central to the pathogenesis of both psoriatic and cardiovascular diseases, and it is likely the basis for a number of other contributions, such as insulin resistance. Due to their interconnectedness, there is no absolute categorization of these various contributions. The organization in the following discussion is to help provide a framework for understanding shared mechanisms between psoriatic diseases and cardiovascular diseases (Fig. 1).
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Inflammation: proposed contribution to cardiovascular diseases
Inflammation is a central factor in the pathogenesis of both psoriatic and cardiovascular diseases, and it is thus believed to be instrumental in the development of psoriatic and cardiovascular comorbidities. Increasing evidence has emerged in support of this theory. Previous studies have established that psoriasis and atherosclerosis involve the same T cell-mediated inflammatory pathways, specifically T-helper 1 (Th-1) and T-helper 17 (Th-17) cascades [42]. First, the localization of Th-1 cells is distinctive of psoriatic and atherosclerotic plaques. In psoriasis, Th-1 cells are recruited from the circulation to the dermis and proceed to activate keratinocytes and inflammatory pathways via interferon (INF)-γ, interleukin (IL)-2, and tumor necrosis factor (TNF)-α. Similarly, the downstream production of INF-γ and TNF-α aids the initiation and progression of atherosclerotic plaques in the systemic vasculature. Alongside Th-1 cells, Th-17 cells act synergistically in the pathogenesis of psoriatic and cardiovascular diseases. Through its production of IL-17, the Th-17 cascade impairs the regulation of inflammation, triggers keratinocyte proliferation, and destabilizes plaques. By way of these T cell pathways, psoriatic diseases are thought to contribute to the development of cardiovascular comorbidities.
Multiple animal studies substantiate these commonalities between psoriatic and cardiovascular diseases. One study of a psoriasiform murine model found that sustained skin inflammation leads to increased aortic inflammation, marked by increased levels of T cells, TNF-α, and IL-17A [43]. Psoriatic skin inflammation is also associated with increased innate lymphoid cells, namely types that produce IL-17A and IL-22 [44]. Another study showed that increased monocyte aggregation is characteristic of psoriatic inflammation and that these monocyte aggregates are specifically recruited to skin sites abundant in TNF-α and IL-17A [45]. Monocytes, recruited during inflammation by monocyte chemoattractant protein-1 (MCP-1), are known to be a key regulator of atherosclerotic lesions through the promotion of arterial smooth muscle proliferation and the formation of foamy macrophages within the vessel wall [46‐49]. Elevated MCP-1 levels are also associated with atherosclerotic plaque instability and rupture, a critical event in adverse cardiovascular outcomes such as myocardial infarction and death [50]. Because monocytes have an established role in the pathogenesis of atherosclerosis and cardiovascular disease, the discovery that monocytes contribute to psoriatic inflammation may be critical in elucidating the true mechanistic link between psoriatic and cardiovascular diseases down to a cytological level. These studies support inflammation as a major contributor to the cardiovascular comorbidities observed in psoriatic diseases.
Further studies on psoriasis patients have provided additional evidence supporting the inflammation theory. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging revealed that both psoriasis and psoriatic arthritis are associated with aortic vascular inflammation [51, 52]. Patients with psoriasis also have increased skin and serum levels of MCP-1 and macrophage-derived chemokine (MDC) [53], as well as increased levels of microparticles originating from endothelial cells, platelets, and monocyte/macrophages [54]. MCP-1, MDC, and microparticles are all molecules involved in cardiovascular inflammation. Thus, these studies lend further weight to the proposed contribution of inflammation in psoriatic and cardiovascular comorbidities.
Contributions of adipokines to inflammatory mechanisms
Adipokines are specialized cytokines released by adipocytes that mediate adipocyte function, inflammation, and the development of cardiometabolic diseases. While some researchers have considered obesity as measured by body mass index as a major contributor to the development of cardiovascular comorbidities with psoriatic diseases, evidence shows that, in obesity, it is the adipokines that play a larger role than the volume of adipocytes. Adiponectin is an adipokine that protects against inflammation, insulin resistance, and atherogenesis [55]. Patients with psoriasis have deficient plasma adiponectin levels independent of cardiometabolic risk factors [55]. Psoriatic tissue also has altered adipose immune cell populations [56]. Thus, while psoriasis is certainly associated with obesity, the link between psoriatic and cardiovascular diseases may be better explained by adipocyte dysfunction. In other words, the dysregulation of adipose tissue inflammation may be the underlying mechanism of psoriatic and cardiovascular comorbidities by promoting a systemic pro-inflammatory state.
Insulin resistance: proposed contribution to cardiovascular diseases
Insulin resistance is another aspect of psoriatic pathogenesis that may largely contribute to the development of cardiovascular comorbidities. As discussed earlier, psoriasis is associated with an increased incidence of diabetes mellitus. Insulin resistance also increases with increasing psoriasis severity [57]. This contribution is central to the “psoriatic march” mechanism pioneered by Dr. Boehncke and others [58]. In this mechanistic pathway, psoriasis causes cardiovascular disease through a series of specific events, namely systemic inflammation, insulin resistance, endothelial dysfunction, and atherosclerosis. Because chronic inflammation is thought to induce insulin resistance, this proposed mechanism has significant overlap with that of inflammation.
While insulin resistance is known to be a risk factor of cardiovascular disease, evidence shows that it also plays a major role in the regulation of keratinocytes in psoriasis. Tissue fluid from psoriatic patients has increased levels of IL-1β, which disrupts insulin-dependent keratinocyte differentiation and induces keratinocyte proliferation [59]. Specifically, IL-1β activates p38MAPK, which results in insulin resistance and keratinocyte abnormalities. Moreover, inflammation-induced resistance to insulin may increase endothelial expression of adhesion molecules, promoting further inflammation in psoriatic plaques [60]. In these ways, insulin resistance plays a major role in the progression of psoriatic disease. Therefore, resistance to insulin could account for the increased cardiovascular risk observed in psoriasis patients.
Dyslipidemia: proposed contribution to cardiovascular diseases
Dyslipidemia, a well-known risk factor for cardiovascular disease, is another major mechanism proposed by researchers as underlying the pathogenesis of cardiovascular comorbidities. As previously discussed, the association between psoriatic diseases and dyslipidemia is unclear. However, this may be due to different definitions and outcomes used to assess “dyslipidemia” in epidemiologic research. Dyslipidemia is defined widely in the primary literature to include elevated total cholesterol, LDL-cholesterol, or triglyceride levels, or reduced HDL cholesterol levels. According to the National Heart, Lung, and Blood Institute of the National Institutes of Health (NHLBI), the cutoff values for cardiovascular risk of total cholesterol, LDL-cholesterol, triglycerides, and HDL cholesterol are defined as greater than 200, 130, 150 mg/dl, or less than 40 mg/dl, respectively [61]. Nevertheless, it is evident that the definition of dyslipidemia varies among individual studies. Therefore, in this particular review, dyslipidemia is defined as intended by the original authors and it should be noted that the definition remains heterogeneous.
Despite the uncertain epidemiologic link between psoriatic diseases and dyslipidemia, there is valuable translational work ongoing to elucidate this potential mechanism. Extensive studies using nuclear magnetic resonance spectroscopy (NMR) have found that patients with psoriasis have an increased concentration of LDL particles, a decreased concentration of HDL particles, and decreased particle size of both LDL and HDL, despite having normal lipid levels [62, 63]. These lipoprotein abnormalities also directly correlate with aortic inflammation after adjusting for cardiovascular risk factors [63]. In addition, it is not just the size of the lipoprotein, but also its function that is important. HDL efflux capacity evaluates the ability of HDL to transport peripheral cholesterol and is thus a measure of function. Studies have shown that HDL efflux capacity is decreased in psoriasis patients [62] and is associated with an increased risk of noncalcified coronary atherosclerosis, independent of HDL cholesterol concentration [64]. These studies suggest that dyslipidemia has a role in the development of psoriatic and cardiovascular comorbidities. It is also possible that standard lipid profiling is not sensitive enough to unmask the important lipid changes that result from psoriasis. Research on lipoprotein characteristics and function may be necessary to refine the mechanistic role of dyslipidemia in the development of cardiovascular diseases with psoriatic diseases.
Angiogenesis and oxidative stress: proposed contribution to cardiovascular diseases
Shared pathways for angiogenesis and reactive oxygen species (ROS)-induced inflammation may also be the basis for cardiovascular comorbidities associated with psoriatic diseases [65]. Marked increases in IL-8 and VEGF are often seen in both psoriasis and atherosclerosis. By creating new vessels, increasing vessel permeability, and recruiting more inflammatory cells to plaque sites, these factors augment the inflammatory response and thus contribute to both psoriatic and cardiovascular disease progression. In particular, VEGF acts on both keratinocytes and endothelial cells, not only promoting the development of psoriatic skin, but also triggering intraplaque neovascularization that destabilizes atherosclerotic plaques. Because these angiogenic factors are common in the pathophysiology of psoriasis and atherosclerosis, they are thought to be critical players in the development of psoriatic and cardiovascular comorbidities.
Similarly, psoriasis and atherosclerosis are associated with the same ROS-signaling cascades. In particular, activation of the JAK-STAT, NF-κB, and MAPK signaling pathways are observed in both disease processes. Additionally, psoriasis and atherosclerosis use the same enzymatic sources of ROS. Thus, shared oxidative mechanisms may account for the cardiovascular complications that often arise with psoriatic diseases through activation of the same biochemical reactions.
Endothelial dysfunction: proposed contribution to cardiovascular diseases
Finally, the theory of endothelial dysfunction is a combination of several contributions already discussed, including inflammation, dyslipidemia, and oxidative stress. Endothelial dysfunction is a pathological state of the vasculature directly correlated with inflammation, oxidative damage, and plaque formation. Compared to the general population, patients with psoriatic diseases have significant endothelial dysfunction, exhibited by intimal thickening, increased stiffness, decreased vasodilation, or decreased elasticity of various parts of the vasculature [66]. Because endothelial dysfunction often precedes the development of cardiovascular disease, it is highly suspected as an all-encompassing mechanism underlying the association of psoriatic diseases with cardiovascular comorbidities.
Conclusion
In conclusion, cardiovascular comorbidities pose a significant problem for the millions of people afflicted with psoriatic diseases. Thus, understanding the epidemiology of psoriatic and cardiovascular diseases as well as their shared pathogenic mechanisms is important for future clinical implications. In summary, both psoriasis and psoriatic arthritis are associated with cardiovascular risk factors, as well as with MACE. Multiple overlapping mechanisms have been proposed in recent literature to explain the contribution of psoriatic diseases to cardiovascular comorbidities, including inflammation, insulin resistance, dyslipidemia, angiogenesis, oxidative stress, and endothelial dysfunction. While our knowledge about the cardiovascular comorbidities associated with psoriatic diseases has advanced, future investigation is necessary to achieve a more complete epidemiological and mechanistic understanding. Ways of enhancing the existing knowledge base in this field include deeper exploration of the mechanistic pathways of pathogenesis and better establishment of quality longitudinal data collection across different populations, potentially through the use of advanced electronic medical records. These endeavors are necessary to achieve a more detailed, accurate understanding of psoriatic and cardiovascular diseases, such that we can apply the findings toward better management of psoriatic diseases and comorbidities clinically.
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Conflict of interest
Ms. Kaitlyn M. Yim declares that she has no conflict of interest. Dr. April W. Armstrong is a consultant for and has received honorariums from Abbvie, Amgen, Celgene, Janssen, Merck, Lilly, Novartis, and Pfizer. Dr. Armstrong has also received grants from Abbvie, Janssen, and Lilly.
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Human participants or animals contents
This article does not contain any studies with human participants or animals performed by any of the authors.